Carbamoyloxylabdane compounds useful in reducing intraocular pressure

ABSTRACT

Novel carbamoyloxylabdanes, intermediates and processes for the preparation thereof, and methods for reducing intraocular pressure and treating cardiac failure utilizing compounds and compositions thereof are disclosed.

This application is a continuation-in-part of U.S. patent applicationSer. No. 947,070, filed Dec. 29, 1986, now abandoned.

The present invention relates to carbomoyloxylabdanes. Moreparticularly, the present invention relates to carbamoyloxylabdanes ofthe formula 1 ##STR1## wherein:

(a) R₁ is hydrogen or a group of the formula ##STR2## wherein R₂ and R₃are independently hydrogen or loweralkyl of 1 to 6 carbon atoms and r is0 or 1; and R₂ and R₃ taken together with the nitrogen atom to whichthey are attached form a group of the formula ##STR3## wherein X is O,S, a group of the formula NR₁₉ wherein R₁₉ is loweralkyl of 1 to 6carbon atoms or a group of the formula CHR₄ wherein R₄ is hydrogen,loweralkyl of 1 to 6 carbon atoms or a group of the formula OR₅ whereinR₅ is hydrogen, loweralkyl of 1 to 6 carbon atoms or a group of theformula ##STR4## wherein R₁₀ is loweralkyl of 1 to 6 carbon atoms and nis 0 or 1;

(b) R₉ is hydrogen;

(c) R₁ and R₉ taken together form a group of the formula CO, a group ofthe formula SO or a group of the formula CHNR₁₁ R₁₂ wherein R₁₁ and R₁₂are each independently loweralkyl of 1 to 6 carbon atoms; and R₁₁ andR₁₂ taken together with the nitrogen atom to which they are attachedform a group of the formula ##STR5## wherein X and n are as above;

(d) R₆ and R₇ are independently hydrogen, a group of the formula##STR6## wherein R₂₀ is hydrogen or loweralkyl of 1 to 6 carbon atoms,or a group of the formula ##STR7## wherein R₁₃ is hydrogen, loweralkylof 1 to 6 carbon atoms, hydroxyloweralkyl of 2 to 6 carbon atoms,loweralkoxyloweralkyl having 1 to 6 carbon atoms in the alkoxy group and2 to 6 carbon atoms in the alkyl group, a group of the formula HOCH₂CH(OH)CH₂ ; R₁₄ is hydrogen, hydroxyl, loweralkoxy of 1 to 6 carbonatoms, loweralkyl of 1 to 6 carbon atoms, hydroxyloweralkyl of 2 to 6carbon atoms, loweralkoxyloweralkyl of 1 to 6 carbon atoms in the alkoxygroup and 2 to 6 carbon atoms in the alkyl group, loweralkanoyl of 2 to6 carbon atoms, loweralkanoylloweralkyl of 2 to 6 carbon atoms in thealkanoyl group and 1 to 6 carbon in the alkyl group, a group of theformula ##STR8## wherein s is 1 or 2, a group of the formula ##STR9## agroups of the formula ##STR10## a group of the formula HOCH₂ CH(OH)CH₂,a group of the formula (CH₂)_(t) NR₂₁ R₂₂ wherein R₂₁ and R₂₂ areindependently loweralkyl of 1 to 6 carbon atoms and t is 0, or 2 to 6,R₂₁ and R₂₂ taken together with the nitrogen atoms to which they areattached form a group of the formula ##STR11## wherein X and n are asabove, a group of the formula OR₂₃ wherein R₂₃ is hydrogen, loweralkylof 1 to 6 carbon atoms, a group of the formula (CH₂)_(t),NR₂₁ R₂₂wherein t' is 2 to 6, R₂₁ and R₂₂ are as above, a group of the formula##STR12## wherein R₂₄ is hydrogen, loweralkyl of 1 to 6 carbon atoms,lowercycloalkyl of 3 to 6 carbon atoms, loweralkenyl of 2 to 6 carbonatoms, haloloweralkenyl of 2 to 6 carbon atoms, loweralkanoylloweralkylof 2 to 6 carbon atoms in the alkanoyl group and 1 to 6 carbon atoms inthe alkyl group, loweralkoxyloweralkyl of 1 to 6 carbon atoms in eachgroup, loweralkoxycarbonylloweralkyl of 1 to 6 carbon atoms in eachgroup, loweralkylamino of 1 to 6 carbon atoms, lowerdialkylamino of 2 to6 carbon atoms, a group of the formula ##STR13## wherein s is as above,a group of the formula ##STR14## a group of the formula (CH₂)_(t),NR₂₁R₂₂ Wherein R₂₁, R₂₂ and t' are as above, a group of the formula##STR15## wherein X and n are as above, a group of the formula (CH₂)_(u)N(R₂₅)COR₂₆, wherein u is 1, 2 or 3 and R₂₅ and R₂₆ are independentlyhydrogen or loweralkyl of 1 to 6 carbon atoms, a group of the formula##STR16## wherein R₂₇ and R₂₈, are loweralkyl of 1 to 6 carbon atoms,with the provisos:

(e) that R₁, R₆ and R₇ are not simultaneously hydrogen,

(f) that when R₁ and R₆ are hydrogen, R₇ is not ##STR17##

(g) that R₆ and R₇ are not simultaneously ##STR18##

(h) that when r is 1, either R₆ or R₇ is ##STR19##

(i) that when R₁ and R₆ are hydrogen, R₁₃ and R₁₄ are not simultaneouslyloweralkyl of 1 to 6 carbon atoms; and

(j) that when R₁ and R₉ taken together form a group of the formula CO,SO or CHNR₁₁ R₁₂, R₆ and R₇ are not simultaneously hydrogen; the opticalor geometric isomers thereof, or the pharmaceutically acceptable saltsthereof, which are useful for reducing intraocular pressure and treatingcardiac failure alone or in combination with inert adjuvants.

Subgeneric to the carbamoyloxylabdanes of the present invention arecompounds of formula 1 wherein:

(a) R₁ is hydrogen and R₇ is a group of the formula ##STR20## whereinR₁₃ and R₁₄ are as above;

(b) R₁ is hydrogen and R₆ is a group of the formula ##STR21## whereinR₁₃ and R₁₄ are as above;

(c) R₁ is a group of the formula ##STR22## wherein R₂, R₃, and r are asabove, and R₆ and R₇ are hydrogen;

(d) R₁ and R₉ taken together form a group of the formula CHNR₁₁ R₁₂wherein R₁₁ and R₁₂ are as above and R₆ or R₇ is a group of the formula##STR23## wherein R₁₃ and R₁₄ are as above;

(e) R₁ is hydrogen, R₆ is hydrogen, R₁₃ is hydrogen and R₁₄ isloweralkyl of 1 to 6 carbon atoms;

(f) R₆ is a group of the formula ##STR24## wherein R₁₃ and R₁₄ are asabove and R₇ is a group of the formula ##STR25## wherein R₂₀ is asabove; and

(g) R₇ is a group of the formula ##STR26## wherein R₁₃ and R₁₄ are asabove and R₆ is a group of the formula ##STR27## wherein R₂₀ is asabove.

(h) R₁₃ is hydrogen and R₁₄ is a groups of the formula ##STR28## whereinR₂₄ is loweralkyl of 1 to 6 carbon atoms or a group of the formula##STR29## wherein n and X are as above.

As used through the specification and appended claims, the term "alkyl"refers to a straight or branched chain hydrocarbon radical containing nounsaturation and having 1 to 8 carbon atoms such as methyl, ethyl,1-propyl, 2-propyl, 1-butyl, 1-pentyl, 2-pentyl, 3-hexyl, 4-heptyl,2-octyl, and the like; the term "alkenyl" refers to a straight orbranched chain hydrocarbon radical containing unsaturation in the formof a single carbon to carbon double bond and having from 2 to 8 carbonatoms such as propenyl, 2-butentyl, 2-methyl-2-butenyl, 3-hexenyl,3-ethyl-2-pentenyl, 3-methyl-3-heptenyl, octenyl, and the like; the term"alkynyl" refers to a straight or branched chain hydrocarbon radicalcontaining unsaturation in the form of a single carbon to carbon triplebond and having from 2 to 8 carbon atoms such as ethynyl, propynyl,2-butynyl, 3-methylbutynyl, 2-hexynyl, 3-heptynyl, octynyl, and thelike; the term "cycloalkyl" refers to a saturated hydrocarbon grouppossessing at least one carbocyclic ring, the ring containing from 3 to8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cyclyheptyl, cyclooctyl, and the like; the term "alkoxy" refers to amonovalent substituent which consists of an alkyl group linked throughan ether oxygen and having its free valence bond from the ether oxygensuch as methoxy, ethoxy, propoxy, butoxy, 1,1-dimethylethoxy, pentoxy,3-methylpentoxy, 2-ethylpentoxy, octoxy and the like; the term"alkanoyl" refers to the radical formed by removal of the hydroxylfunction from an alkanoic acid. Examples of alkanoyl groups are formyl,acetyl, propionyl, 2,2-dimethylacetyl, hexanoyl, octanoyl, and the like.The term "alkanol" refers to a compound formed by a combination of analkyl group and a hydroxy radical. Examples of alkanols are methanol,ethanol, 1- and 2-propanol, 1,2-dimethylethanol, hexanol, octanol andthe like. The term "alkanoic acid" refers to a compound formed bycombination of a carboxyl group with a hydrogen atom or alkyl group.Examples of alkanoic acids are formic acid, acetic acid, propanoic acid,2,2-dimethylacetic acid, hexanoic acid, octanoic acid, and the like; theterm "halogen" refers to a member of the family consisting of fluorine,chloroine, bromine or iodine. The term "lower" as applied to any of theaforementioned groups refers to a group having a carbon skeletoncontaining up to and including 6 carbon atoms.

In the formula presented herein the various substituents are illustratedas joined to the labdane nucleus by one of two notations: a solid line(--) indicating a substituent which is in the β-orientation (i.e., abovethe plane of the molecule) and a broken line (---) indicating asubstituent which is in the α-orientation (i.e., below the plan of themolecule). The formulas have all been drawn to show the compounds intheir absolute stereochemical configuration. Inasmuch as the startingmaterials having a labdane nucleus are naturally occurring or arederived from naturally occuring materials, they, as well as the finalproducts, have a labdane nucleus existing in the single absoluteconfiguration depicted herein. The processes of the present invention,however, are intended to apply as well to the synthesis of labdanes ofthe racemic series.

In addition to the optical centers of the labdane nucleus, thesubstituents thereon may also contain chiral centers contributing to theoptical properties of the compounds of the present invention andproviding a means for the resolution thereof by conventional methods. Awavy line (˜) connecting a group to a chiral center indicates that thestereochemistry of the center is unknown, i.e., the group may exist inany of the possible orientations. The present invention comprehends alloptical isomers and racemic forms of the compounds of the presentinvention where such compounds have chiral centers in addition to thoseof the labdane nucleus.

The novel labdanes of the present invention are synthesized by theprocessess illustrated in Reaction Schemes A and B.

To prepare a carbamoyloxylabdane 4, an8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one-1,9-dialkylformamideacetal 2, the synthesis of which is described in U.S. patent applicationSer. No. 848,053, filed Apr. 4, 1986, is carbamoylated to provide a7β-carbamoyloxylabdaneformamide acetal 3 which is hydrolyzed to a7β-carbamoyloxy-1α,6β, 9α-trihydroxylabdane 4.

The carbamoylation is accomplished by treating a 6β, 7β-dihydroxylabdane2 with 1,1'-carbonyldiimidazole 8 ##STR30## in an alkyl alkanoate or ahalocarboin to afford an imidazolocarbonyloxylabdane of formula 9##STR31## which, preferably without isolation, is treated with an amineof formula 10

    R.sub.13 R.sub.14 NH                                       10

wherein R₁₃ and R₁₄ are as above, neat, in an alkyl alkanoate,halocarbon or a mixture of a halocarbon and an alkanol to yield 4. Amongalkyl alkanoates there may be mentioned methyl acetate, ethyl acetate,methyl propionate, ethyl propionate and the like. Ethyl acetate ispreferred. Among halocarbons there may be mentioned dichloromethane,trichloromethane and the like. Dichloromethane is preferred. Amongalkanols there may be mentioned methanol, ethanol, 2-propanol and thelike. Methanol is preferred and mixtures of dichloromethane and methanolare also preferred. While the temperature at which the carbamoylation isperformed is not narrowly critical, it is preferred to carry out thereaction at a temperature between about 0° C. to about 50° C., mostpreferrably at a temperature of about 25° C.

If desired, the intermediate imidazolocarbonyloxylabdane 9 may beisolated by workup of the reaction mixture prior to the addition ofamine 10 by methods well-known in the art. For example, the intermediatelabdane 9 may be isolated by chromatography on a suitable column (e.g.,silica gel) with an appropriate eluent such as hexane/ethyl acetate.

While the relative amounts of 6β,7β-dihydroxylabdane 2 and1,1'-carbonyldiimidazole 8 are not narrowly critical in thecarbamoylation process, i.e., in the conversion of 2 to 4 via a7-imidazolocarbonyloxylabdane 9, it is desirable to employ about onemolar equivalent of each reactant to maximize the formation of themonosubstituted imidazolo precursor 9 of the monosubstitutedcarbamoyloxylabdane 4. When about two molar equivalents of1,1'-carbonyldiimidazole 8 to one molar equivalent of6β,7β-dihydroxylabdane 8 are employed, a6β,7β-bis-imidazolocarbonyloxylabdane 9a is formed.

The hydrolysis is achieved by contracting a7β-carbamoyloxylabdaneformamide acetal 3 with aqueous alkanol, or withan aqueous alkanoic acid in alkanol, or a mineral acid in aqueousalkanol. Included among aqueous alkanoic acids are aqueous formic acid,aqueous acetic acid, aqueous propionic acid and the like. Included amongmineral acids are hydrochloric acid, hydrobromic acid, sulfuric acid,nitric acid and the like. Included among alkanols are methanol, ethanol,2-propanol and the like. A reaction medium consisting of about 80%aqueous acetic acid and methanol or aqueous methanol is preferred. Thehydrolysis proceeds readily at a temperature within the range of about0° C. to about 50° C. in 80% aqueous acetic acid, and above 40° C. to90° C. in aqueous methanol. The preferred hydrolysis temperatures inaqueous acetic acid and aqueous methanol are about 25° C. and 65° C.,respectively.

Alternatively, the carbamoylation of a 6β,7β-dihydroxylabdaneformamideacetal 2 is effected by treating such a labdane 2 with a base, forexample, an alkali metal bis(trialkylsilyl)amide of formula 11

    [(R.sub.17).sub.3 Si].sub.2 NLi                            11

wherein R₁₇ is loweralkyl in an organic solvent, for example, anethereal solvent, to form an alkali metal alkoxide of 2, followed bytreatment with either an isocyanate of formula 12

    R.sub.13 NCO                                               12

wherein R₁₃ is as hereinbeforedescribed or a carbamoyl halide of formula13 ##STR32## wherein R₁₃ and R₁₄ are as hereinbeforedescribed and Hal ishalogen, neat or in an ethereal solvent, to provide a7β-carbamoyloxylabdane 3. Examples of alkali metalbis(trialkylsilyl)amides include lithium, sodium or potassiumbis(trimethylsilyl)- or bis(triethylsilyl)amides and the like. Examplesof ethereal solvents are diethyl ether, 1,2-dimethoxyethane, dioxane,tetrahydrofuran and the like. A reaction medium consisting of lithiumbis(trimethyl)silylamide and tetrahydrofuran is preferred. The formationof the alkali metal alkoxide is preformed at a temperature within thenon-critical range of about -25° C. to about 50° C., preferably at atemperature of about 0° C. to about 25° C. The condensation of an alkalimetal alkoxide of 2 with either an isocyanate 12 or a carbamoyl halide13 is performed at a temperature of about 0° C. to about the refluxtemperature of the reaction medium, preferrably at about 25° C. to thereflux temperature.

To prepare a 6β-carbamoyloxylabdane of formula 5, a 7β-carbamoylabdaneof formula 4 is rearranged by means of an alkali metal alkoxide in analkanol or ethereal solvent, alone or combination, at a temperaturewithin the range of about 0° C. to about 50° C., a temperature of about25° C. being preferred. Suitable alkali metal alkoxides include lithium,sodium and potassium 2-propoxides, lithium, sodium and potassium2,2-dimethylethoxides and the like. Suitable alkanols include2-propanol, 2,2-dimethylethanol and the like. Suitable ethereal solventsinclude diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran, dioxane andthe like. Potassium 2,2-dimethylethoxide and a combination of2,2-dimethylethanol and tetrahydrofuran is the preferred rearrangementmedium.

To prepare a carbamoyloxy-6β,7β,9α-trihydroxylabdane of formula 7,8,13-epoxy-1α,6β,7β, 9α-tetrahydroxylabd-14-en-11-one 6, the synthesisof which is described in U.S. Pat. No. 4,134,986, issued Jan. 16, 1979to B. S. Bajwa, et al., is contacted with 1,1'-carbonyldiimidazole 8 inan ethereal solvent such as tetrahydrofuran followed by an amine 10wherein R₁₃ and R₁₄ are R₂ and R₃, respectively, under conditionssubstantially similar to those employed for the conversion of6β,7β-dihydroxylabdane-1α,9α-formamide acetal 2 to a7β-carbamoyloxylabdane 3, as hereinbeforedescribed.

To construct a carbamoyloxylabdane having a 1α,9α-sulfite or carbonatefunction, i.e., a compound of formula 15 wherein R₁₃ and R₁₄ are asabove and Y is SO or CO, and8,13-epoxy-1α,6β,7β,9α-tetrahydroxylabdane-14-en-11one-1α, 9α-sulfite or-carbonate 14, the preparation of which is described in by N. J. deSouza, et al., Medicinal Research Reviews, 3, 201 (1983), may be treatedwith 1,1'-carbonyldiimidazole 8 followed by an amine of formula 10, oran alkoxide of 13 may be condensed with an isocyanate 12 or carbamoylhalide 13, all steps being performed by processess substantially similarto those describedherein for the related conversion of 7β-hydroxylabdane2 to 7-carbamoyloxylabdane 3.

Similarly, to fabricate a carbamoyloxy labdane characterized by thepresence of a 1α,9α-sulfite function and, for example, a7β-(N-alkanoylaminocarbonyloxy) group, a7β-aminocarbonyloxy-1α,9α-dihydroxylabdane 4 wherein R₁₃ and R₁₄ arehydrogen is converted to a7β-aminocarbonyloxy-1α,9α-dihydroxy-1α,9α-sulfite 15 which is condensedwith an alkanoic acid anhydride of formula 19 ##STR33## wherein R₂₆ isalkyl to a7β-N-alkanoylaminocarbonyloxy)-1α,9α-dihydroxylabdane-1.alpha.,9α-sulfite17. See Reaction Scheme C.

The introduction of the 1α, 9α-sulfite is accompolished by treating a1α,9α-dihydroxylabdane 4 with thionyl chloride 8 in the presence ofpyridine or a tertiary amine and an inert solvent. Among tertiaryamines, there may be mentioned trailkylamines such as trimethylamine,triethylamine, tripropylamine and the like, and heteroaromatic aminessuch as pyridine, picoline, lutidine, collidine and the like.Trialkylamines are preferred. Triethylamine is most preferred. Amonginert solvents, there may be mentioned halocarbons such asdichloromethane, trichloromethane, 1,1- and 1,2-dichloroethane and thelike. Dichloromethane is preferred. While the reaction temperature atwhich the sulfite introduction is performed is not critical, it ispreferred to conduct the reaction at a temperature of about 10° to about40° C., a reaction temperature of about 25° C. being most preferred.

The condensation is effected by contacting a7β-(aminocarbonyloxy)labdane 17 with an anhydride 19 in the presence ofa mineral acid or a sulfonic acid. Included among mineral acids aresulfuric acid, nitric acid, hydrochloric acid and the like. Includedamong sulfonic acids are methanesulfonic acid, hexanesulfonic acid,p-toluenesulfonic acid and the like. Mineral acids are preferred.Sulfuric acid is most preferred. The condensation is preferablyperformed at about 25° C. Reduced or elevated temperature, however, inthe range of about 10° C. to about 40° C. may be employed.

To gain entry into the labdane series characterized by the presence of a7β-(N-alkanoylaminocarbonyloxy) function and a 1α,9α-dihydroxy moiety,i.e., a compound of formula 18, a7β-(N-alkanoylaminocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one17-1,9-carbonate is subjected to hydrolytic processes. Hydrolysis, forexample, is achieved by contacting a 1α,9α-carbonate 17 with water in anappropriate solvent such as pyridine, picoline, lutidine, collidine andthe like, pyridine being preferred. The hydrolysis is generallyconducted at the reflux temperature of the reaction medium. It may,however, be performed at temperatures from room temperature to thereflux temperature of the medium.

To introduce an N-(alkylaminoalkylcarbonyloxy) function at the1α-position of the labdane nucleus, i.e., to prepare, for example, alabdane of formula 21 wherein R₂,R₃,R₁₃, R₁₄, and r are ashereinbeforedefined, a 7β-carbamoyloxy-1α-hydroxylabdane 4 is acylatedto a 1α-haloacetoxy-7β-carbamoyloxylabdane 20 which is aminated to 21.See Reaction Scheme D.

The acylation utilizing a haloalkylalkanoyl halide of formula 22##STR34## wherein r is 1 and Hal is chloro, bromo or iodo is conductedin the presence of a dialkylaniline such as dimethylaniline,diethylaniline and the like in a halocarbon such as dichloromethane,trichloromethane, 1,1- or 1,2-dichloroethane, 1,1- or1,2-dichloroethylene and the like at a reaction temperature from about0° to about 50° C. Dimethylaniline and dichloromethane is the preferredreaction medium. A temperature within the range from about 0° to about25° C. is the preferred reaction temperature. The1α-haloalkylcarbonyloxylabdane 20 is isolated by conventional work-up ofthe reaction mixture, e.g., extraction and evaporation.

The amination is accomplished by contacting a1α-haloalkylcarbonyloxylabdane 20 with an alkylamine of formula 23

    R.sub.2 R.sub.3 NH                                         23

wherein R₂ and R₃ are as hereinbeforedisclosed in an alkyl alkanoate ata temperature from about 5° to about 55° C., a reaction temperature ofabout 25° C. being preferred. Included among alkyl alkanoates are methylacetate, ethyl acetate, methyl propionate, ethyl propionate and thelike. Ethyl acetate is the preferred alkyl alkanoate.

To synthesize a 7β-(N-acyloxyaminocarbonyloxy)labdane of formula 25, a7β-(N-hydroxyaminocarbonyloxy)labdane 24 is condensed with a carboxylicacid of formula 26

    R.sub.18 CO.sub.2 H                                        26

wherein R₁₈ is as hereinbeforedefined in the presence of1,1'-carbonyldiimidazole 8 in a halocarbon such as dichloromethane,trichloromethane, 1,1- or 1,2-dichloroethane, 1,1- or1,2-dichloroethylene and the like, or an alkyl alkanoate such as methylacetate, ethyl acetate, methyl propionate, ethyl propionate and the likeat a reaction temperature within the range of about 5° to about 50° C.The preferred solvents are dichloromethane and ethyl acetate. Anethereal cosolvent, e.g. tetrahydrofuran, dioxane, diethyl ether,dimethoxyethane and the like may be employed when a halocarbon is usedas the reaction medium. Tetrahydrofuran is the preferred cosolvent. Thepreferred reaction temperature is about 25° C. In the event, an aminoacid 26 in the form of its hydrohalide salt, i.e., an amino acid whereinR₁₈ is characterized by the presence of a basic amine function isutilized as a reactant, an acid acceptor such as, for example, atrialkylamine is also employed in the reaction medium. Included amongtrialkylamines are trimethylamine, triethylamine, tripropylamine and thelike. Triethylamine is the preferred acid acceptor.

A carbodiimide of formula 27

    R.sub.28 N═C═NR.sub.29                             27

wherein R₂₈ is dialkylaminoalkyl and R₂₉ is alkyl may be employed as thecondensing agent instead of the carbonylimidazole 8 in the process forthe conversion of 24 to 25. An acid acceptor, e.g., a4-dialkylaminopyridine such as 4-dimethylamnopyridine is utilized when ahydrohalide salt of carbodiimide 27 is employed as a the condensingagent.

In the alternative, a 7β-(N-acyloxyaminocarbonyloxy)labdane 25 isprepared from a 7β-(N-hydroxyaminocarbonyloxy)labdane 24 by the mixedanhydride method. For example, treatment of8,13-epoxy,7β-(hydroxyaminocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one24 wherein R₁ and R₁₃ are hydrogen with the mixed anhydride of acrylicacid or methylacylic acid and 2,2-dimethylpropionic acid of formulas 28or 28a ##STR35## prepared, in situ, by contacting acrylic acid with2,2-dimethylpropionyl chloride in the presence of triethylamine as anacid acceptor and dichloromethane as the reaction solvent, indichloromethane containing tetrahydrofuran as a cosolvent and4-dimethylaminopyridine as an acid scavenger and/or catalyst affords7β-(N-acryloyloxyaminocarbonyloxy)-8,11-epoxy-1α,6β,9.alpha.-trihydroxylabd-14-en-11-one25 wherein R₁ is hydrogen, R₁₃ is hydrogen and R₂₄ is acrylyl.

A 7β-(N-carbamoylaminocarbonyloxy)labdane, for example, a labdane offormula 25 wherein R₂₄ is dialkylamino, more particularly dimethylamino,is elaborated by the carbamoyl halide method. Thus, treatment of a7β-(N-hydroxyaminocarbonyloxy)labdane 24 with an N,N-dialkylcarbamoylhalide of formula 29 ##STR36## wherein R₃₀ and R₃₁ are alkyl and Hal ischloro, bromo or iodo, more particularly N,N-dimethylcarbamoyl chloride,i.e., a compound of formula 29 wherein R₃₀ and R₃₁ are dimethyl and Halis chloro, in a halocarbon such as, for example, dichloromethane, and anacid acceptor such as, for example, triethylamine, provides a7-substituted labdane wherein R₂₄ is N,N-dialkyl, more particularly,N,N-dimethyl.

To prepare a labdane substituted at the 7-position by an(alkylcarbonylalkyl)aminocarbonyloxy function, i.e., to prepare acompound of formula 1 wherein R₁₄ is alkanoylalkyl, an appropriatesecondary carbinol, for example, a compound of formula 30 wherein R₁ andR₉ taken together form a group of the formula CHNR₁₁ R₁₂ wherein R₁₁ andR₁₂ are as hereinbeforedefined is oxidized by the oxalylchloride-dimethylsulfoxide complex in the presence of an acid acceptorsuch as triethylamine at a reduced temperature within the range of about-60° to about -50° C. to afford a7β-[N-(2-oxopropyl)aminocarbonyloxy]abdane 31 wherein R₁ and R₉ are asabove. The 1α,9α-dimethylformamide acetal protecting group is cleaved byhydrolysis processes hereinbeforedescribed to provide the1α,9α-dihydroxylabdane substituted at the 7β-position by the aforesaidcarbonyloxy group, i.e., a compound of formula 31 wherein R₁ and R₉ arehydrogen.

To introduce an aminocarbonyloxy function at the 6-position of thelabdane nucleus, i.e., to prepare, for example, a compound of formula34, a labdane-formamide acetal 32 (R₁ and R₉ taken together form a groupof the formula CHNR₂ R₃ where R₂ and R₃ are alkyl) is acylated withdiimidazole 8 in the presence of an amine 10 to provide a6β-aminocarbonyloxylabdanedialkylformamide acetal 34 (R₁ and R₉ form agroup of the formula CHNR₂ R₃ wherein R₂ and R₃ are alkyl) which ishydrolyzed to a 6β-aminocarbonyloxy-1α,7β,9α-trihydroxylabane 34 whereinR₁ and R₉ are hydrogen. The acylation is carried out by treating 32 withdiimidazole 8 in a halocarbon such as, e.g., dichloromethane,trichloromethane, tetrachloromethane, 1,1- or 1,2-dichloroethane, 1,1-or 1,2-dichloroethane, 1,1- or 1,2-dichloroethylene and the like, analkyl alkanoate such as e.g., methyl acetate, ethyl acetate, ethylpropionate and the like, or an ethereal solvent such as, e.g.tetrahydrofuran, dioxane, diethyl ether and the like, in the presence ofa tertiary amine such as e.g., a trialkylamine (i.e., trimethylamine,triethylamine, tripropylamine, lutidine, collidine or the like, or aheteroaromatic amine such as, e.g. pyridine, picoline and the like,followed by an amine 10 at a reaction temperature of from about 0° C. tothe reflux temperature of the solvent system. The preferred solvent is ahalocarbon, dichloromethane being most preferred. The preferred reactiontemperature is about 25° C.

To promote formation of the 6β-carbamoyloxylabdane, 34, the initialstage of the conversion of 32 to 34, i.e., the treatment of 32 withdiimidazole 8 in the presence of a tertiary amine is allowed to proceedfor an extended period of time, preferably for about 12 to about 36hours, most preferably for about 24 hours. The intermediate6β,7β-dihydroxylabdane-6β,7β-carbonate 33 is isolated and, in turn,treated with amine 10 to form 6β-carbamoyloxylabadane 34, or theconversion may be conducted in situ, preferably in situ.

A 6β-carbamoyloxy-7β-hydroxylabdane 34 (wherein R₁ and R₉ together areCHNR₁₁ R₁₂ wherein R₁₁ and R₁₂ are alkyl) may be acylated to a7β-alkanoyloxy-6β-carbamoyllabdane 35 (wherein R₁ and R₉ together areCHNR₁₁ R₁₂ wherein R₁₁ and R₁₂ are alkyl) by, for example, an alkanoicacid anhydride 19 such as acetic acid anhydride 19 (wherein R₂₆ ismethyl) in an alkanoic acid such as acetic acid 26 (wherein R₁₈ ismethyl) in the presence of a tertiary amine such as4-dimethylamnopyridine to provide a7β-alkanoyloxy-6β-carbamoyloxylabdane 35 (wherein R₁ and R₂ are asabove) such as a 7β-acetoxy-6β-carbamoyloxylabdane 35 (such as a7β-acetoxy-6β-carbamoyloxylabdane 35 (wherein R₁ and R₉ are as above).

A 6β-alkanoyloxy-7β-hydroxylabdane 37 (wherein R₁ and R₉ taken togetherare CHNR₁₁ R₁₂ wherein R₁₁ and R₁₂ are alkyl), the preparation of whichis described in U.S. patent application Ser. No. 849,053, now U.S. Pat.No. 4,639,443, granted Jan. 27, 1987, may be carbamoylated to a6β-alkanoyloxy-7β-carbamoyloxy labdane 38 (wherein R₁ and R₉ are asabove) by, for example, the procedure hereinbeforedescribed for theconversion 2 to 3.

By following the hydrolytic processes hereinbeforedescribed for thecleavage of the 1α,9α-dihydroxy-1α,9α-dialkylformamide acetal group, a6α-carbamoyloxylabdane 34 wherein R₁ and R₉ together are CHNR₁₁ R₁₂wherein R₁₁ and R₁₂ are alkyl is converted to a6β-carbamoyloxy-1α,9α-dihydroxylabdane 34 wherein R₁ and R₉ arehydrogen.

Similarly, by following these hydrolytic processes, the1α,9α-dihydroxy-1α,9α-dialkylformamide acetal group of7β-alkoxy-6β-carbamoyloxylabdane 35 (wherein R₁ and R₉ together areCHNR₁₁ R₁₂ wherein R₁₁ and R₁₂ are alkyl) may be cleaved to thecorresponding 1α,9α-dihydroxy derivatives 35 and 36 (wherein R₁ and R₉are hydrogen) (see Reaction Schemes E and F). A reduced hydrolysistemperature of about 25° C. may be employed.

The carbamoyloxylabdanes of the present invention are useful in thetreatment of glaucoma by virtue of their ability to reduce elevatedintraocular pressure in a glaucomatous subject as determined by themethod described by J. Caprioli, et al., Invest. Ophthalmol. Vis. Sci.,25, 268 (1984). The results of the determination expressed as percentdecrease of outflow pressure is presented in Table I.

                  TABLE I                                                         ______________________________________                                                         CONCEN-   DECREASE IN                                                         TRATION   OUT FLOW                                           COMPOUND         (%)       PRESSURE (%)                                       ______________________________________                                        8,13-epoxy-7β-(N-methyl-                                                                  0.25      59                                                 aminocarbonyloxy)-1α,6β,9α-                                  trihydroxylabd-14-en-11-                                                      one                                                                           7β-(aminocarbonyl-                                                                        0.50      41                                                 oxy)-8,13-epoxy-1α-                                                     6β,9α-trihydroxylabd-                                              14-en-11-one                                                                  8,13-epoxy-7β-(2-                                                                         0.25      50                                                 hydroxyethylamino-                                                            carbonyloxy)-1α,6β,9α-                                       trihydroxylabd-14-en-                                                         11-one                                                                        7β-acetoxy-8,13-epoxy-                                                                    1.0       51                                                 1α,6β,9α-trihydroxylabd-                                                      0.1       23                                                 14-en-11-one                                                                  ______________________________________                                    

Intraocular pressure reduction is achieved when the presentcarbamoyloxylabdanes are administered to a subject requiring suchtreatment as an effective topical dose of a 0.01 to 3.0% solution orsuspension. A particularly effective amount is about 3 drops of a 0.25%preparation per day. It is to be understood, however, that for anyparticular subject, specific dosage regimens should be adjustedaccording to the individual need and the professional judgment of theperson administering or supervising the administration of the aforesaidcompound. It is to be further understood that the dosages set forthherein are exemplary only and that they do not, to any extent, limit thescope or practice of the invention.

The carbamoyloxylabdanes of the present invention are also useful in thetreatment of cardiac failure by virtue of their ability to elicit apositive ionotropic effect as evidenced by an increase in contractileforce in an isolated guinea pig atria assay, the electrically-drivenguinea pig left atrium assay, which is performed as follows:

Male guinea pigs weighing 200-300 grams are stunned with a blow to theback of the head. The heart is rapidly removed and placed in a petridish containing Krebs solution. The ventricle is separated from theatria, the atria are sectioned into the right and left atria anddouble-O silk ligatures are tied to the apex of the left atrium. Theatrium is fixed to a pair of platinum plate electrodes and suspended ina 20-ml tissue bath containing Kreb's solution aerated with 95%oxygen-5% carbon dioxide at 37° C. One end of the atrium is fixed to ahook in the electrode and the other end is connected to a Grass FT03force displacement transducer. Resting tension and stabilization timeare the same as described above. The atrium is stimulated at 3 Hz, 0.5msec duration at supramaximal voltage (constant current) via a Grass S88stimulator and constant current unit. Force of contraction iscontinuously displaced on a Gould recorder. Test drug is prepared as insection A and is added to the tissue baths in the same fashion. Changein contractile force from baseline is determined for each concentration,and the change in contractile force (g) is plotted against accumulateddrug concentration (ug/ml). The activity of the test drug, i.e., theincrease in contractile force (g) from the stabilized force expressedthe percentage change at a given concentration is determinedgraphically, as is the ED₅₀ -value, i.e., the extrapolated dose (ug/ml)which increases the contractile force by 50% over the stabilized rate.

Results obtained in these assays for representative carbamoyllabdanesand a reference compound as presented in Table II.

                  TABLE II                                                        ______________________________________                                                                  IONOTROPIC                                                                    ACTIVITY                                                                      CHANGE (%) OF                                                                 CONTRACTILE                                         COMPOUND      CONC (ug/ml)                                                                              FORCE (g)                                           ______________________________________                                        8,13-epoxy-7β-[N-                                                                      0.414.sup.1 50                                                  2,2-(dimethylpro-                                                             pionyloxy)amino-                                                              carbonyloxy)-                                                                 1α,6β,9α-                                                    trihydroxylabd-                                                               14-en-11-one                                                                  8,13-eppxy-7β-[N-                                                                      0.28.sup.1  50                                                  propionyloxyamino-                                                            carbonyloxy)-1α,6β,-                                               9α-trihydroxylabd-                                                      14-en-11-one                                                                  8,13-epoxy-7β-[N-                                                                      0.046.sup.1 50                                                  (1-methylpiperidino-                                                          carbonyloxy]-1α,6β,-                                               9α-trihydroxylabd-                                                      14-en-11-one                                                                  8,13-epoxy-7β-[N-                                                                      0.058.sup.1 50                                                  (3-hydroxypropyl)-                                                            aminocarbonyloxy]-                                                            1α,6β,9α-trihydroxy-                                         labd-14-en-11-one                                                             7β-acetoxy-8,13-                                                                       0.073.sup.1 50                                                  epoxy-1α,6β,9α-                                              trihydroxylabd-                                                               14-en-11-one                                                                  ______________________________________                                         .sup.1 extrapolated ED.sub.50value                                       

Cardiac failure treatment is achieved when the presentcarbamoyloxylabdanes are administered to a subject requiring suchtreatment as an effective oral, parenteral or intravenous dose of 0.01to 100 mg/kg of body weight per day. A particularly effective amount isabout 25 mg/kg of body weight per day. It is to be understood, however,that for any particular subject, specific dosage regimens should beadjusted according to the individual need and the professional judgmentof the person administering or supervising the administration of theaforesaid compound. It is to be further understood that the dosage setforth herein are examplary only and that they do not, to any extent,limit the scope or practice of the invention.

Compounds of the present invention include:

(a)1α-(Aminocarboxyloxy)-8,13-epoxy-6β,7β9α-trihydroxylabd-14-en-11-one;

(b)8,13-Epoxy-1α-(N-methylaminocarbonyloxy)-6β,7β,9α-trihydroxylabd-14-en-11-one;

(c)8,13-Epoxy-1α-(4-morpholinocarbonyloxy)-6β,9α-trihydroxylabd-14-en-11-one;

(d)8,13-Epoxy-1α-(4-thiomorpholinocarbonyloxy)-6β,7β,9α-trihydroxylabd-14-en-11-one;

(e)8,13-Epoxy-1α-(4-hydroxy-1-piperidinocarbonyloxy)-6β,7β,9.alpha.-trihydroxylabd-14-en-11-one;

(f)8,13-Epoxy-1α-(4-methoxy-1-piperidinocarbonyloxy)-6β,7β,9.alpha.-trihydroxylabd-14-en-11-one;

(g)8,13-Epoxy-1α-(4-acetoxy-1-piperidinocarbonyloxy)-6β,7β,9.alpha.-trihydroxylabd-14-en-1-one;

(h)8,13-Epoxy-7β-(4-thiomorpholinocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one-1,9-carbonate;

(i)8,13-Epoxy-7β-(4-methoxy-1-piperidinocarbonyloxy)-1α,6β,9.alpha.-trihydroxylabd-14-en-11-one-1,9-sulfite;

(j)8,13-Epoxy-6β-(4-thiomorpholinocarbonyloxy)-1α,7β,9α-trihydroxylabd-14-en-11-one-1,9-(4-thiomorpholine)formamideacetal;

(k)8,13-Epoxy-7β-(4-methoxy-1-piperidinocarbonyloxy)-1α,6β,9.alpha.-trihydroxylabd-14-en-11-one-1,9-(4-morpholino)formamideacetal;

(l)8,13-Epoxy-7β-(4-acetoxy-1-piperidinocarbonyloxy)-1α,6β,9.alpha.-trihydroxylabd-14-en-11-one-1,9-(4-acetoxy-1-piperidine)formamideacetal;

(m)7β-[2-(2-Dimethylaminoethyl)aminocarbonyloxy]-8,13-epoxy-1α,6.beta.,9α-trihydroxylabd-14-en-11-one;

(n)7β-[N-(3-Dimethylaminopropyl)aminocarbonyloxy]-8,13-epoxy-1α,6.beta.,9α-trihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal;

(o)7β-[N-(3-Dimethylaminopropyl)aminocarbonyloxy]-8,13-epoxy-1α,6.beta.,9α-trihydroxylabd-14-en-11-one;

(p)7β-[N-(3-Dimethylaminopropionyloxy)aminocarbonyloxy]-8,13-epoxy-1.alpha.,6β,9α-trihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal;

(q)7β-[N-(3-Dimethylaminopropionyloxy)aminocarbonyloxy]-8,13-epoxy-1.alpha.,6β,9α-trihydroxylabd-14-en-11-one;

(r)7β-[N-(4-Dimethylaminobutynyloxy)aminocarbonyloxy]-8,13-epoxy-1.alpha.6,β9α-trihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal;

(s)7β-(N-dimethylaminoacetoxy)aminocarbonyloxy-8,13-epoxy-1α,6.beta.,9α-trihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal;

(t)7β-(N-dimethylaminoacetoxy)aminocarbonyloxy-8,13-epoxy-1α,6.beta.,9α-trihydroxylabd-14-en-11-one;

(u)8,13-Epoxy-7β-[N-(4-methylpiperazinylcarbonyloxy)-aminocarbonyloxy]-1α,6β,9α-trihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal;

(v)8,13-Epoxy-7β-[N-(4-methylpiperazinylcarbonyloxy)aminocarbonyloxy]-1.alpha.,6β,9α-trihydroxylabd-14-en-11-one;

(w)8,13-Epoxy-7β-[N-(2-morpholinoethyl)aminocarbonyloxy]-1α,6.beta.,9α-trihydroxylabd-14-en-11-one;

(x)8,13-Epoxy-7β-[N-(2-morpholinoethyl)aminocarbonyloxy]-1α,6.beta.,9α-trihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal;

(y)7β-[N-(2-Dimethylaminoethylaminocarbonyloxy)aminocarbonyloxy]-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal;

(z)7β-[N-(2-Dimethylaminoethylaminocarbonyloxy)aminocarbonyloxy]-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one;

(a')8,13-Epoxy-6β-(N-propionyloxyaminocarbonyloxy)-1α,7β,9.alpha.-trihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal;

(b')8,13-Epoxy-6β-(N-propionyloxyaminocarbonyloxy)-1α,7β,9.alpha.-trihydroxylabd-14-en-11-one;

(c')8,13-Epoxy-7β-(N-methylaminoacetoxyaminocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one;

(d')6β-Acetoxy-8,13-epoxy-7β-[(N-3-(dimethylaminopropyl)aminocarbonyloxy]-1α,9α-dihydroxylabd-14-en-11-one;and

(e')7β-Acetoxy-8,13-epoxy-6β-[N-3-(dimethylaminopropyl)aminocarbonyloxy]-1α,9α-dihydroxylabd-14-en-11-one.

The carbamoyloxylabdanes of the present invention are also useful in thetreatment of hypertension, congestive heart failure, bronchial asthmaand psoriasis.

Effective amounts of the compounds of the present invention may beadministered to a subject by any one of various methods, for example,orally as in capsules or tablets, parenterally in the form of sterilesolutions or suspensions, in some cases intravenously in the form ofsterile solutions, or suspensions, and topically in the form ofsolutions, suspensions or ointments and by aerosol spray.

Effective quantities of the compounds of the invention may beadministered orally, for example, with an inert diluent or with anedible carrier. They may be enclosed in gelatin capsules or compressedinto tablets. For the purpose of oral therapeutic administration, theaforesaid compounds may be incorporated with excipients and used in theform of tablets, troches, capsules, elixirs, suspensions, syrups,wafers, chewing gums and the like. These preparations should contain atleast 0.5% of active compound, but may be varied depending upon theparticular form and may conveniently be between 4% to about 70% of theweight of the unit. The amount of active compound in such composition issuch that a suitable dosage will be obtained. Preferred compositions andpreparations according to the present invention are prepared so that anoral dosage unit form contains between 0.1-30 milligrams of the activecompound.

The tablets, pills, capsules, troches and the like may also contain thefollowing ingredients: a binder such as microcrystalline cellulose, gumtragacanth or gelatin an excipient such as starch or lactose, adisintegrating agent such as alginic acid, corn starch and the like; alubricant such as magnesium stearate; a glidant such as colloidalsilicon dioxide; and a sweetening agent such as sucrose or saccharin ora flavoring agent such as peppermint, methyl salicylate, or orangeflavoring may be added. When the dosage unit form is a capsule, it maycontain, in addition to materials of the above type, a liquid carriersuch as a fatty oil. Other dosage unit forms may contain other variousmaterials which modify the physical form of the dosage unit, forexample, as coatings. Thus, tablets or pills may be coated with sugar,shellac, or other enteric coating agents. A syrup may contain, inaddition to the active compounds, sucrose as a sweetening agent andcertain preservatives, dyes and colorings and flavors. Materials used inpreparing these various compositions should be pharmaceutically pure andnon-toxic in the amounts used.

For the purpose of oral, parenteral or topical therapeuticadministration, the active compounds of the invention may beincorporated into a solution, suspension, ointment or cream. Thesepreparations should contain at least 0.01% of active compound, but maybe varied between 0.1 and about 5% of the weight thereof. The amount ofactive compounds in such compositions is such that a suitable dosagewill be obtained. Preferred compositions and preparations according tothe present invention are prepared so that a parenteral or topicaldosage unit contains between 0.01 to 10 milligrams of active compound.

The solutions or suspensions for topical or parenteral administrationmay also include the following components: A sterile diluent such aswater for injection, saline solution, fixed oils, polyethylene glycols,glycerine, propylene glycol or other synthetic solvents; antibacterialagents such as benzyl alcohol or methyl parabens; antioxidants such asascorbic acid or sodium bisulfite; chelating agents such asethylenediaminetetraacetic acid; buffers such as acetates, citrates orphophates and agents for the adjustment of tonicity such as sodiumchloride or dextrose. The parenteral preparation can be enclosed inampules or disposable syringes; the topical preparation may be enclosedin multiple dose vials or dropping bottles, made of glass or plastic.

The compounds of the present invention, while effective themselves, maybe formulated and administered in the form of their pharmaceuticallyacceptable addition salts for purposes of stability, convenience orcrystallization, increased solubility and the like.

Preferred pharmaceutically acceptable addition salts include salts ofmineral acids, for example, hydrochloric acid, sulfuric acid, nitricacid and the like, salts of monobasic, carboxylic acids such as, forexample, acetic acid, propionic acid and the like, salts of dibasiccarboxylic acids such as, for example, maleic acid, fumaric acid and thelike, and salts of tribasic carboxylic acids such as, for example,carboxysuccinic acid, citric acid and the like.

The following Examples are for illustrative purposes only. Alltemperatures are given in degrees Centigrade.

EXAMPLE 17β-(Aminocarbonyloxy)-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal

A solution of 484 mg of8,13-epoxy--1α,6β,7β,9α-tetrahydrolabd-14-en-11-one-1,9-dimethylformamideacetal in 10 ml of ethyl acetate containing 202.5 mg of1,1'-carbonyldiimidazole was stirred at ambient temperature overnight.Anhydrous ammonia was bubbled into the mixture for 1 min and the mixturewas stirred at ambient temperature for 48 to 72 hr in a sealed vessel.The mixture was filtered and evaporated. The residue was flashchromatographed on silica gel in hexane:ethyl acetate (1:1). Theappropriate fractions were combined and evaporated. The residue wasrecrystallized from hexane:ether to afford 148 mg (26.9%) of product, mp98°-122°.

ANALYSIS: Calculated for C₂₄ H₃₈ N₂ O₇ : 61.77%C, 8.23%H, 6.00%N. Found:61.73%C, 8.42%H, 5.49%N.

EXAMPLE 28,13-Epoxy-7β-(N-methylaminocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal

To a solution of 100 mg of8,13-epoxy-1α,6β,7β,9α-tetrahydroxylabd-14-en-11-one-1,9-dimethylformamideacetal in 10 ml of tetrahydrofuran was added 23 μ1 of a 1M solution oflithium bis(trimethylsilyl)amide in tetrahydrofuran. Methyl isocyanate(14 μ1, 13.5 mg) was added to the mixture and the mixture was stirred atambient temperature under nitrogen overnight. The mixture was quenchedwith 100 μ1 of water and evaporated. The residue was flashchromatographed on silica gel in hexane:ethyl acetate (1:1). Theappropriate fractions were combined and evaporated to yield 30 mg(26.4%) of product, mp 189°-191°.

ANALYSIS: Calculated for C₂₅ H₄₀ N₂ O₇ : 62.47%C, 8.41%H, 5.83%N. Found:62.59%C, 8.44%H, 5.65%N.

EXAMPLE 38,13-Epoxy-7β-(4-morpholinocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal

A solution of 500 mg of8,13-epoxy-1α,6β,7α,9α-tetrahydroxylabd-14-en-11-one-1,9-dimethylformamideacetal in 10 ml of ethyl acetate containing 202.5 mg of1,1'-carbonyldiimidazole was stirred at ambient temperature undernitrogen over the weekend. Morpholine (500 ml) was added and the mixturewas stirred at ambient temperature for 24 hr. The mixture was dilutedwith 100 ml of ethyl acetate and washed with 0.01N hydrochloric aciduntil the aqueous washings remained acidic. The organic phase was washedwith saturated aqueous sodium bicarbonate solution, dried over anhydroussodium sulfate, filtered and evaporated. The residue was flashchromatographed on silica gel in hexane:ethyl acetate (1:1). Theappropriate fractions were combined and evaporated to yield 180 mg(27.3%) of product, mp 75°-100°.

ANALYSIS: Calculated for C₂₈ H₄₄ N₂ O₅ : 62.65%C, 8.28%H, 5.22%N. Found:62.60%C, 8.34%H, 5.07%N.

EXAMPLE 48,13-Epoxy-7β-(4-hydroxy-1-piperidinocarbonyloxy)-1α,6β,9.alpha.-trihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal

A solution of 500 mg of8,13-epoxy-1α,6β,7β,9α-tetrahydroxylabd-14-en-11-one-1,9-dimethylformamideacetal in 10 ml of ethyl acetate containing 202.5 mg of1,1'-carbonyldiimidazole was stirred at ambient temperature undernitrogen for 48 to 72 hr. 4-Hydroxypiperidine (505 mg) was added and themixture was stirred at ambient temperature for 24 hr. The mixture wasdiluted with 100 ml of ethyl acetate and washed with 0.01N hydrochloricacid until the aqueous washings remained acidic. The organic layer waswashed with saturated aqueous sodium bicarbonate solution, dried overanhydrous sodium sulfate, filtered and evaporated. The residue was flashchromatographed on silica gel in hexane:ethyl acetate (1:2). Theappropriate fractions were combined and evaporated to yield 342.5 mg(51.9%) of product, mp 70°-100°.

ANALYSIS: Calculated for C₂₉ H₄₆ N₂ O₈ : 63.24%C, 8.44%H, 5.08%N. Found:63.23%C, 8.50%H, 4.99%N.

EXAMPLE 58,13-Epoxy-7β-(2-hydroxyethylaminocarbonyloxy)-1α,6β,9.alpha.-trihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal

A solution of 1.5 g of8,13-epoxy-1α,6β,7β,9α-tetrahydroxylabd-14-en-11-one-1,9-dimethylformamideacetal in 30 ml of ethyl acetate containing 607.5 mg of1,1'-carbonyldiimidazole was stirred under nitrogen at ambienttemperature for 24 hr. A 10 ml-portion of this mixture was combined witha solution of 359.9 mg of 2-aminoethanol in 1 ml of ethyl acetate, andthe resultant mixture was stirred for 2 days. The mixture was dilutedwith ethyl acetate to 100 ml and extracted several times with 0.01Nhydrochloric acid until the aqueous washings remained acidic. The ethylacetate layer was washed with saturated aqueous sodium bicarbonatesolution, dried over anhydrous sodium sulfate, filtered and evaporated.The residue was flash chromatographed on silica gel in hexane:ethylacetate:methanol (10:10:1). The appropriate fractions were combined andevaporated and the residue was crystallized from hexane:ether to afford201.3 mg (33.4%) of product, mp 100°-110°.

ANALYSIS: Calculated for C₂₆ H₄₂ N₂ O₈ : 61.15%C, 8.31%H, 5.48%N Found:60.77%C, 8.34%H, 5.20%N.

EXAMPLE 67β-(2,3-Dihydroxypropylaminocarbonyloxy)-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal

A solution of 1.5 g of8,13-epoxy-1α,6β,7β,9α-tetrahydroxylabd-14-en-11-one-1,9-dimethylformamideacetal was dissolved in 30 ml of ethyl acetate containing 607.5 mg of1,1'-carbonyldiimidazole and stirred under nitrogen at ambienttemperature for 24 hr. A 10 ml-portion of this mixture was combined witha solution of 536.9 mg of 2,3-dihydroxypropylamine in 1 ml of ethylacetate and the resultant mixture was stirred for 2 days. The reactionmixture was diluted with ethyl acetate to 100 ml and extracted with0.01N hydrochloric acid until the aqueous washings remained acidic. Theorganic phase was washed with saturated aqueous sodium bicarbonatesolution, dried over anhydrous sodium sulfate, filtered and evaporated.The residue was flash chromatographed on silica gel in hexane:ethylacetate:methanol (10:10:1). The appropriate fractions were combined andevaporated. The residue was crystallized from hexane:ether to afford189.6 mg (29.8%) of product, mp 90°-100°.

ANALYSIS: Calculated for C₂₇ H₄₄ N₂ O₉ : 59.97%C, 8.22%H, 5.18%N. Found:59.72%C, 8.20%H, 4.97%N.

EXAMPLE 77β-(N,N-Dimethylcarbamoyloxy)-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal

8,13-Epoxy-1α,6β,7β,9α-tetrahydroxylabd-14-en-11-one-1,9-dimethylformamideacetal (500 mg) was dissolved in 50 ml of dry tetrahydrofuran undernitrogen and cooled to 0° in an ice-bath. Lithiumbis(trimethylsilyl)amide (1.4 ml of a 1M tetrahydrofuran solution) wasadded and the mixture was stirred at 0° for 1 hr. Dimethylcarbamoylchloride (254 mg) was added to the mixture followed by gradual heatingto reflux. The mixture was heated under reflux overnight and allowed tocool to ambient temperature. Water (100 ml) was added and the reactionmixture was evaporated. The residue was flash chromatographed on silicagel eluting first with 300 ml of hexane:ethyl acetate (2:1) then with400 ml of hexane:ethyl acetate (1:1). The appropriate fractions werecombined and evaporated. The residue was dried under vacuum to provide231.7 mg (39.2%) product as an amorphous solid, mp 70°-80°.

ANALYSIS: Calculated for C₂₆ H₄₂ N₂ O₇ : 63.12%C, 8.58%H, 5.66%N. Found:63.52%C, 8.62%H, 5.30%N.

EXAMPLE 87β-(N,N-Diethylcarbamoyloxy)-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal

To a stirred solution of 1.0 g of8,13-epoxy-1α,6β,7β,9α-tetrahydrolabd-14-en-11-one-1,9-dimethylformamideacetal in 100 ml of dry tetrahydrofuran under nitrogen at 0° was added2.83 ml of 1M lithium bis(trimethylsilyl)amide in tetrahydrofuran. Thesolution was stirred 20 min at 0° . To the solution was added 0.62 ml(0.66 g) of N,N-diethylcarbamoyl chloride. The solution was heated toambient temperature, then to reflux and reflux was continued for 24 hr.The solution was allowed to cool to ambient temperature, poured intoice/water, diluted with ether, washed three times with water, once withsaturated sodium chloride solution, and dried over anhydrous sodiumsulfate. Filtration followed by evaporation of solvent provided an oil.The oil was dissolved in a minimum volume of 30% n-butyl acetate/hexaneand flash chromatographed on silica gel. The column was eluted with 30%n-butyl acetate/hexane, 40% n-butyl acetate/hexane and 50% n-butylacetate/hexane. The appropriate fraction was concentrated and theresidue was crystallized from cyclohexane to provide 24 mg (18.9%) ofproduct.

ANALYSIS: Calculated for C₂₈ H₄₆ N₂ O₇ : 64.34%C, 8.87%H, 5.36%N. Found:64.50%C, 8.97%H, 5.25%N.

EXAMPLE 98,13-Epoxy-7β-(N-hydroxylaminocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal

8,13-Epoxy-1α,6β,7β,9α-tetrahydrolabd-14-en-11-one-1,9-dimethylformamideacetal (500 mg) was dissolved in 10 ml of dichloromethane together with202.5 mg of 1,1'-carbonyldiimidazole under nitrogen. The mixture wasstirred at ambient temperature overnight. Hydroxylamine hydrochloride(1.6 g) was dissolved in 25 ml of methanol together with a singlecrystal of phenophthalein. Sufficient 25% sodium methoxide in methanolwas added to turn the color of the solution pink. The sodium chloridewas allowed to settle. An aliquot of 6 ml of the hydroxylamine solutionin methanol was added to the original solution and the mixture wasstirred for 1 hr. The mixture was diluted with chloroform and extractedtwice with water, once with 0.01N hydrochloric acid and one with dilutesodium bicarbonate. The organic phase was dried over anhydrous sodiumsulfate, filtered, and evaporated. The residue was flash chromatographedon silica gel in hexane:ethyl acetate (1:1), followed by hexane:ethylacetate (1:2). The appropriate fractions were combined and evaporatedand the residue was crystallized from hexane:ether to yield 200 mg(35.2%) of product, mp 119°-139°.

ANALYSIS: Calculated for C₂₄ H₃₈ N₂ O₈ : 59.72%C, 7.95%H, 5.80%N. Found:59.46%C, 8.09%H, 5.41%N.

EXAMPLE 108,13-Epoxy-7β-(N-methyl-N-hydroxylaminocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal

8,13-Epoxy-1α,6β,7β,9α-tetrahydroxylabd-14-en-11-one-1,9-dimethylformamideacetal (500 mg) was dissolved in 10 ml of dichloromethane together with202.5 mg of 1,1'-carbonyldiimidazole under nitrogen. The mixture wasstirred at ambient temperature overnight. N-Methylhydroxylaminehydrochloride (3.6 g) was dissolved in 25 ml of methanol together with asingle crystal of phenophthalein. Sufficient 25% sodium methoxide inmethanol was added to change the color of the solution pink. The sodiumchloride was allowed to settle out. An aliquot of 6 ml of theN-methylhydroxylamine in methanol solution was added to the originalsolution and the mixture was stirred for 1 hr. The mixture was dilutedwith chloroform and the solution was washed twice with water, once with0.01N hydrochloric acid and once with dilute sodium bicarbonatesolution. The organic phase was dried over anhydrous sodium sulfate,filtered and evaporated. The residue was flash chromatographed on silicagel in hexane:ethyl acetate (2:1) (1 l) and hexane/ethyl acetate (1:1).The appropriate fractions were combined and evaporated. The residue wascrystallized from hexane:ether to yield 200 mg (34.2%) of product, mp105°-119°.

ANALYSIS: Calculated for C₂₅ H₄₀ N₂ O₅ : 60.46%C, 8.13%H, 5.64%N. Found:60.75%C, 8.54%H, 5.29%N.

EXAMPLE 118,13-Epoxy-7β-(N-ethylaminocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal

To a solution of 1.0 g of8,13-epoxy-1α,6β,7β,9α-tetrahydrolabd-14-en-11-one-1,9-dimethylformamideacetal in 100 ml of dry tetrahydrofuran was added 0.237 ml of 1M lithiumbis(trimethylsilyl)amide in tetrahydrofuran. The solution was stirredfor 0.5 hr at ambient temperature. To the solution was added 0.336 g ofethyl isocyanate. The solution was stirred at reflux under nitrogen for18 hr and allowed to cool to ambient temperature. The solution wasdiluted with ethyl acetate, poured into ice/water, extracted twice withethyl acetate, washed with water, saturated sodium chloride solution anddried over anhydrous sodium sulfate. Filtration followed by evaporationof solvent provided an oil. The oil was dissolved in a minimum volume of40% ethyl acetate;hexanes and flash chromatographed on silica gel usingthe same solvent system. Evaporation of solvent from the appropriatefractions provided 747 mg (63.5%) of product.

ANALYSIS: Calculated for C₂₆ H₄₂ N₂ O₇ : 63.13%C, 8.56%H, 5.67%N. Found:62.90%C, 8.88%H, 5.47%N.

EXAMPLE 128,13-Epoxy-7β-(N-methoxylaminocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal

8,13-Epoxy-1α,6β,7β,9α-tetrahydroxylabd-14-en-11-one-1,9-dimethylformamideacetal (500 mg) was dissolved in 10 ml of dichloromethane together with202.5 mg of 1,1'-carbonyldiimidazole, and the mixture was stirred undernitrogen at ambient temperature overnight. Methoxylamine hydrochloride(3.6 g) was dissolved in 25 ml of methanol together with a crystal ofphenophthalein and sufficient 25% sodium methoxide in methanol was addedto change the color of the solution to just pink. A 6.0 ml-aliquot ofthe methoxylamine solution was added to the original mixture and theresultant mixture was stirred under nitrogen at ambient temperatureovernight. The reaction mixture was evaporated and the residue was flashchromatographed on silica gel in hexane:ethyl acetate (2:1). Evaporationof the appropriate fractions gave 144.3 mg (24.7%) of product, as anamorphous solid, mp 85°-92°.

ANALYSIS: Calculated for C₂₅ H₄₀ N₂ O₈ : 60.46%C, 8.13%H, 5.64%N. Found:60.24%C, 8.42%H, 5.41%N.

EXAMPLE 138,13-Epoxy-7β-(1-pyrrolidinocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal

A solution of 500 mg of8,13-epoxy-1α,6β,7β,9α-tetrahydroxylabd-14-en-11-one-1,9-dimethylformamideacetal in 50 ml of tetrahydrofuran containing 202.5 mg of1,1'-carbonyldiimidazole was stirred at ambient temperature undernitrogen overnight. Pyrrolidine 417 μl (355 mg) was added and themixture was stirred under nitrogen at ambient temperature for 3 hr andallowed to stand at ambient temperature for two and one-half days. Themixture was quenched with water and evaporated. The residue wasdissolved in ether. The mixture was washed with water, dilute potassiumcarbonate solution, dried over anhydrous sodium sulfate and filtered.The filtrate was evaporated and the residue was flash chromatographed onsilica gel in hexane:ethyl acetate (1:1). The appropriate fractions werecombined and the residue was crystallized from hexane-ether to provide30 mg (4.81%) of product, mp 218°-220°.

EXAMPLE 147β-(Aminocarbonyloxy)-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one

A solution of 128.4 mg of7β-(aminocarbonyloxy)-8,13-epoxy-1α,6β,9α-trihydroxy-14-en-11-one-1,9-dimethylformamideacetal in 2 ml of 80% acetic acid and 2 ml of methanol was stirred atambient temperature for 36 hrs. The mixture was evaporated and theresidue was flash chromatographed on silica gel in hexane:ethyl acetate(1:1). The appropriate fractions were combined and evaporated. Theresidue was crystallized from hexane:ether to afford 50 mg (44.2%) ofproduct, mp 124°-145°.

ANALYSIS: Calculated for C₂₁ H₃₃ NO₇ : 61.28%C, 8.10%H, 3.40%N. Found:61.09%C, 7.99%H, 3.35%N.

EXAMPLE 158,13-Epoxy-7β-(N-methylaminocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one

A solution of 291.6 mg of8,13-epoxy-7β-(N-methylaminocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal in 6 ml of methanol:80% acetic acid (1:1) was stirred overnightunder nitrogen at ambient temperature. The mixture was evaporated. Theresidue was suspended in ethyl acetate washed with aqueous sodiumbicarbonate solution and evaporated. The residue was flashchromatographed on silica gel in hexane:ethyl acetate (1:1). Theappropriate fractions were combined and evaporated. The residue wascrystallized from hexane:ether to afford 67.4 mg (54.4%) of product, mp133°-154°.

ANALYSIS: Calculated for C₂₂ H₃₅ NO₇ : 62.09%C, 8.31%H, 3.29%N. Found:61.35%C, 8.08%H, 3.17%N.

EXAMPLE 168,13-Epoxy-7β-(4-morpholinocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one

A solution of 265.0 mg of8,13-epoxy-7β-(4-morpholinocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal in a mixture of 2 ml of 80% acetic acid and 2 ml of methanol wasstirred at ambient temperature for 36 hr. The mixture was evaporated andthe residue was flash chromatographed on silica gel in hexane:ethylacetate (1:1). The appropriate fractions were combined and evaporated.The residue was crystallized from hexane:ether to provide 158.2 mg(65.8%) of product, mp 180°-188°.

ANALYSIS: Calculated for C₂₅ H₃₉ NO₈ : 62.34%C, 8.18%H, 2.91%N. Found:62.33%C, 8.11%H, 2.80%N.

EXAMPLE 178,13-Epoxy-7β-(4-hydroxy-1-piperidiniocarbonyloxy)-1α,6β,9.alpha.-trihydroxylabd-14-en-11-one

A solution of 306.1 mg of8,13-epoxy-7β-(4-hydroxy-1-piperidinocarbonyloxy)-1α,6β,9.alpha.-trihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal in 2 ml of 80% acetic acid and 2 ml of methanol was stirred for36 hr at ambient temperature. The solvent was evaporated and the residuewas flash chromatographed on silica gel in hexane:ethyl acetate (1:2).The appropriate fractions were combined and evaporated. The residue wascrystallized from hexane:ether to afford 185.1 mg (67.2%) of product, mp145°-156°.

ANALYSIS: Calculated for C₂₆ H₄₁ NO₈ : 63.00%C, 8.35%H, 2.82%N. Found:62.71%C, 8.40%H, 2.79%N.

EXAMPLE 188,13-Epoxy-7β-(1-pyrrolidinocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one

A solution of 300 mg8,13-epoxy-7β-(1-pyrrolidinocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal in 5 ml of 80% aqueous acetic acid and 5 ml of methanol wasstirred at ambient temperature for 18 hr under nitrogen. The solvent wasevaporated under vacuum. The residue was suspended in ethyl acetate andwashed with saturated aqueous sodium bicarbonate solution. The ethylacetate layer was evaporated and the residue was flash chromatographedon silica gel in hexane:ethyl acetate (2:1). The appropriate fractionswere combined and evaporated. The residue was crystallized fromhexane:ethyl acetate to afford 88.1 mg (31.6%) of product, mp 230°-233°.

ANALYSIS: Calculated for C₂₅ H₃₉ NO₇ : 64.48%C, 8.46%H, 3.01%N. Found:64.44%C, 8.48%H, 3.15%N.

EXAMPLE 198,13-Epoxy-7β-(2-hydroxyethylaminocarbonyloxy)-1α,6β,9.alpha.-trihydroxylabd-14-en-11-one

8,13-Epoxy-7β-(2-hydroxyethylaminocarbonyloxy)-1α,6β,9.alpha.-trihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal (200 mg) was dissolved in a mixture of 2 ml of methanol and 2 mlof 80% acetic acid and stirred at ambient temperature under nitrogen for3 days. The mixture was evaporated and the residue was flashchromatographed on silica gel in hexane:acetone (2:1). The appropriatefractions were combined, evaporated and crystallized from hexane:ethylacetate to afford 92.4 mg (51.8%) of product, mp 116°-120°.

ANALYSIS: Calculated for C₂₃ H₃₇ NO₅ : 60.63%C, 8.20%H, 3.07%N. Found:60.47%C, 8.44%H, 3.14%N.

EXAMPLE 207β-(N-2,3-Dihydroxypropylaminocarbonyloxy)-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one

7β-(N-2,3-Dihydroxypropylaminocarbonyloxy)-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal (200 mg) was dissolved in a mixture of 2 ml of methanol and 2 mlof 80% acetic acid. The mixture was stirred under nitrogen at ambienttemperature for 4 days. The mixture was evaporated and the residue flashchromatographed on silica gel in hexane:acetone (1:1). The appropriatefractions were combined and evaporated. The residue was crystallizedfrom hexane:n-butyl acetate to afford 74.8 mg (41.6%) of product, mp90°-105°.

ANALYSIS: Calculated for C₂₄ H₃₉ NO₉ : 59.35%C, 8.11%H, 2.88%N. Found:58.89%C, 8.29%H, 2.71%N.

EXAMPLE 218,13-Epoxy-7β-(N-hydroxylaminocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one

8,13-Epoxy-1α,6β,7β,9α-trihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal (1 g) was dissolved in 20 ml of dry dichloromethane together with405 mg of 1,1'-carbonyldiimidazole, and the mixture was stirred undernitrogen overnight. Hydroxylamine (303.6 mg) generated from thehydrochloride in methanol by adding methanolic sodium methoxide wasadded to the original solution, and the resultant mixture was stirredovernight. The mixture was evaporated and the residue was flashchromatographed on silica gel in hexane:ethyl acetate (1:2). Thefractions were combined and the residue was dissolved in 10 ml ofmethanol and 1 ml of 2N hydrochloric acid, and the mixture was stirredat ambient temperature under nitrogen overnight. The mixture wasevaporated. The residue was partitioned between saturated aqueous sodiumbicarbonate and ethyl acetate. The ethyl acetate phase was dried overanhydrous sodium sulfate, filtered and evaporated. The residue was flashchromatographed on silica gel in hexane:ethyl acetate (1:1). Theappropriate fractions were combined and evaporated. The residue wascrystallized from hexane:ether to afford 152.0 mg (15.1 %) of product,mp 209°-211°.

ANALYSIS: Calculated for C₂₁ H₃₃ NO₈ : 58.99%C, 7.80%H, 3.27%N. Found:58.85%C, 8.08%H, 3.24%N.

EXAMPLE 228,13-Epoxy-7β-(N-methylhydroxylaminocarbonyloxy)-1α,6β,9.alpha.-trihydroxylabd-14-en-11-one

8,13-Epoxy-7β-(N-methylhydroxylaminocarbonyloxy)-1α,6β,9.alpha.-trihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal (200 mg) was dissolved in 2 ml of 80% acetic acid and 2 ml ofmethanol. The mixture was stirred at ambient temperature under nitrogenfor 36 hr and evaporated. The residue was dissolved in chloroform andextracted with saturated aqueous sodium bicarbonate solution. Theorganic phase was loaded onto a flash chromatography column of silicagel packed in hexane:ethyl acetate (2:1) and eluted with the samesolvent mixture. The appropriate fractions were combined and evaporated.The residue was crystallized from hexane:ether to afford 90 mg of(50.6%) of product, mp 110°-145°.

ANALYSIS: Calculated for C₂₂ H₃₅ NO₈ : 59.84%C, 7.99%H, 3.17%N. Found:59.77%C, 7.94%H, 2.94%N.

EXAMPLE 238,13-Epoxy-7β-(N-ethylaminocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one

A solution of 0.742 mg of8,13-epoxy-7β-(N-ethylaminocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal in 10 ml of methanol and 10 ml of 80% acetic acid was stirred atroom temperature for 48 hr. The solution was diluted with ethyl acetate,washed three times with water and once with saturated sodium chloridesolution. The solution was dried over anhydrous sodium sulfate, filteredand concentrated. The residue was dissolved in 1:1 n-butylacetate/hexanes and flash chromatographed on silica gel. The initialfractions were combined and concentrated. The residue crystallized toprovide 109 mg of product, mp 165°-167°. Subsequent fractions werecombined and concentrated to provide an additional 163 mg of product.The total yield of product was 272 mg (41.3%).

ANALYSIS: Calculated for C₂₃ H₃₇ NO₇ : 62.85%C, 8.45%H, 3.15%N. Found:62.79%C, 8.47%H, 3.07%N.

EXAMPLE 248,13-Epoxy-7-β(N-methoxylaminocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one

8,13-Epoxy-7β-(N-methoxylaminocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal (121.5 mg) was dissolved in 2 ml of 80% acetic acid together with2 ml of methanol. The mixture was stirred at ambient temperature undernitrogen for 36 hr. The solvent was evaporated and the residue was flashchromatographed on silica gel eluting with hexane:ethyl acetate (65:35).The appropriate fractions were combined and evaporated. Crystallizationof the residue from hexane:ether provided 40 mg (37%) of product, mp100°-120°.

ANALYSIS: Calculated for C₂₂ H₃₅ NO₈ : 59.84%C, 7.99%H, 3.17%N. Found:60.03%C, 8.20%H, 2.94%N.

EXAMPLE 258,13-Epoxy-7β-(N,N-bis-2-hydroxyethylaminocarbonyloxy)-1α,6.beta.,9α-trihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal

To a stirred solution of 2.0 g of8,13-epoxy-1α,6β,7β,9α-tetrahydroxylabd-14-en-11-one-1,9-dimethylformamideacetal in 30 ml of dry ethyl acetate under nitrogen was added 0.814 g of1,1'-carbonyldiimidazole. The solution was stirred at room temperatureovernight. To the solution was added 2 ml of N,N-diethanolamine. Thesolution was stirred 24 hr at ambient temperature and flashchromatographed on silica gel. The column was eluted with 1/1 ethylacetate/hexanes, 2/1 ethyl acetate/hexanes and ethyl acetate. Theappropriate fractions were combined and concentrated to provide 0.34 g(17%) of product, as a foam, mp 97°-119°.

ANALYSIS: Calculated for C₂₈ H₄₆ N₂ O₉ : 60.63%C, 8.36%H, 5.05%N. Found:60.90%C, 8.28%H, 4.97%N.

EXAMPLE 268,13-Epoxy-6β-(N-methylaminocarbonyloxy)-1α,7β,9α-trihydroxylabd-14-en-11-one

To a solution of 0.3 g of8,13-epoxy-7β-(N-methylaminocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-onein 10 ml of t-butanol and 1 ml of dry tetrahydrofuran was added 1.1 g ofpotassium t-butoxide. The solution was stirred for 1 hr at roomtemperature, poured into ice/water, washed twice with water, once withsaturated sodium chloride solution and dried over anhydrous sodiumsulfate. Filtration followed by evaporation of solvent provided an oil.The oil was dissolved in a minimum volume of 1:1 ethyl acetate:hexanesand chromatographed on silica gel eluting with 1:1 ethylacetate:hexanes, followed by 3:2 ethyl acetate:hexanes. The appropriatefractions were combined and concentrated to an oil, which crystallizedon standing to provide, after drying at 111° (1 mm), 180 mg (60%) ofproduct, mp 242°-243°.

ANALYSIS: Calculated for C₂₂ H₃₅ NO₇ : 62.09%C, 8.29%H, 3.29%N. Found:62.29%C, 8.24%H, 2.87%N.

EXAMPLE 278,13-Epoxy-1α-(1-pyrrolidinocarbonyloxy)-6β,7β,9α-trihydroxylabd-14-en-11-one

A solution of 100 mg of8,13-epoxy-1α,6β,7β,9α-tetrahydroxylabd-14-en-11-one was dissolved in 10ml of dry tetrahydrofuran containing 44 mg of 1,1'-carbonyldiimidazolewas stirred at ambient temperature under nitrogen for 1.5 hr.Pyrrolidine (83 μl, 71 mg) was added and the mixture was stirredovernight. The mixture was evaporated and the residue was suspended inether, washed with dilute aqueous hydrochloric acid, water and diluteaqueous potassium carbonate. The ether phase was dried over anhydroussodium sulfate, filtered and evaporated. The residue was flashchromatographed on silica gel in hexane:ethyl acetate (2:1). Theappropriate fractions were combined and evaporated. The residue wasrecrystallized from cyclohexane:ethyl acetate to afford 40.0 mg (31.6%)of product, mp 207°-210°.

ANALYSIS: Calculated for C₂₅ H₃₉ NO₇ : 64.48%C, 8.46%H, 3.01%N. Found:64.62%C, 8.68%H, 3.12%N.

EXAMPLE 288,13-Epoxy-7β-(N-propionylaminocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one

8,13-Epoxy-7β-(N-propionylaminocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one-1,9-carbonate(1.6 g) was dissolved in 20 ml of pyridine and 20 ml of water. Thesolution was heated at reflux for 7 hrs and allowed to cool. Thereaction mixture was diluted with 50 ml of methylene chloride and washedwith 0.01N hydrochloric acid and water. The organic layer was dried overanhydrous sodium sulfate and the solvent was removed under reducedpressure. The residue was chromatographed on silica gel. The column waseluted with hexane:ethyl acetate (3:2). The appropriate fractions werecollected and the solvent was removed to give 660 mg (44%) of product,mp 115°-120°.

ANALYSIS: Calculated for C₂₄ H₃₇ NO₈ : 61.63%C, 7.99%H, 2.99%N. Found:61.18%C, 8.00%H, 2.65%N.

EXAMPLE 298,13-Epoxy-7β-[N-(2-pyridylacetoxy)aminocarbonyloxy]-1α,6β,9α-trihydroxylabd-14-en-11-onehydrochloride

To a stirred solution of 243 mg of 2-pyridylacetic acid hydrochloride in25 ml of methylene chloride was added 0.2 ml of triethylamine. Themixture was stirred at room temperature for 0.5 hr and 227 mg of1,1'-carbonyldiimidazole was added. After 45 mins a solution of 500 mgof8,13-epoxy-7β-(hydroxyaminocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-onein 5 ml of tetrahydrofuran and 25 ml of methylene chloride was added andthe mixture was stirred overnight under a nitrogen atmosphere. Themixture was concentrated under reduced pressure and the residue waschromatographed on silica gel. The column was eluted with 1:1hexane:ethyl acetate. The appropriate fractions were collected and thesolvent was removed. The residue was dissolved in ether (50 ml) andethereal hydrogen chloride was added. The precipitate was collected anddried to give 390 mg (57%) of product, mp 142° (dec).

ANALYSIS: Calculated for C₂₈ H₃₉ ClN₂ O₉ : 57.66%C, 6.75%H, 4.80%N.Found: 57.35%C, 7.12%H, 4.72%N.

EXAMPLE 308,13-Epoxy-7β-[N-(4-methoxysuccinyl)oxyaminocarbonyloxy]-1α,6.beta.,9α-trihydroxylabd-14-en-11-one

To a stirred solution of 740 mg of mono-methylsuccinate in 100 ml ofmethylene chloride was added 910 mg of 1,1'-carbonyldiimidazole. Thesolution was stirred for 45 mins at room temperature under a nitrogenatmosphere.8,13-Epoxy-7β-(hydroxyaminocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one(2.0 g) dissolved in 20 ml of tetrahydrofuran and 100 ml of methylenechloride was added and the resulting mixture was stirred 16 hrs. Themixture was concentrated and the residue was chromatographed on silicagel. The column was eluted with hexane:ethyl acetate (1:1). Theappropriate fractions were collected and the solvent removed to give 1.6g (63%) of product, mp 82°.

ANALYSIS: Calculated for C₂₆ H₃₉ NO₁₁ : 57.65%C, 7.27%H, 2.58%N. Found:57.62%C, 7.24%H, 2.49%N.

EXAMPLE 318,13-Epoxy-7β-[N-(N',N'-dimethylcarbamoyloxy)aminocarbonyloxy]-1.alpha.,6β,9α-trihydroxylabd-14-en-11-one

To a stirred solution of 1.0 g of8,13-epoxy-7β-(hydroxyaminocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-onein 90 ml of methylene chloride and 10 ml of tetrahydrofuran was added283 mg of triethylamine followed by 308 mg of N,N-dimethylcarbamoylchloride dissolved in 10 ml of methylene chloride. The mixture wasstirred overnight at room temperature under a nitrogen atmosphere andthen washed with 0.01N hydrochloric acid, saturated sodium bicarbonatesolution and water. The organic layer was separated, dried overanhydrous sodium sulfate and the solvent was removed. The residue waschromatographed on silica gel. The column was eluted with hexane:ethylacetate (1:1). The appropriate fractions were collected and the solventwas removed to give 390 mg of product, mp 119°-120°.

ANALYSIS: Calculated for C₂₄ H₃₈ N₂ O₉ : 57.80%C, 7.69%H, 5.62%N. Found:57.40%C, 7.70%H, 5.55%N.

EXAMPLE 328,13-Epoxy-7β-[(2-dimethylphosphinyl)ethylcarbonyloxy]aminocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-onehydrate

To a stirred solution of 316 mg of 2-(carboxyethyl)dimethylphosphineoxide in 40 ml of methylene chloride was added 340 mg of1,1'-carbonyldiimidazole. The solution was stirred at room temperaturefor 45 mins under a nitrogen atmosphere.8,13-Epoxy-7β-(hydroxyaminocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one(750 mg) dissolved in 5 ml of tetrahydrofuran and 35 ml of methylenechloride was added and the mixture was stirred for 16 hrs. The reactionmixture was washed with water and saturated sodium bicarbonate solution.The organic portion was separated, dried over anhydrous sodium sulfate,filtered, and the solvent was removed to give 440 mg (45%), mp 201°-203°after crystallization from hexane:ethyl acetate.

ANALYSIS: Calculated for C₂₆ H₄₂ NO₁₀ P: 54.05%C, 7.69%H, 2.43%N. Found:54.32%C, 7.37%H, 2.44%N.

EXAMPLE 338,13-Epoxy-7β-[N-(tetrahydro-2-furoyloxy)aminocarbonyloxy]-1α,6.beta.,9α-trihydroxylabd-14-en-11-one

To a stirred solution of 650 mg of tetrahydro-2-furoic acid dissolved in75 ml of methylene chloride was added 910 mg of1,1'-carbonyldiimidazole. The mixture was allowed to stir at roomtemperature under an atmosphere of nitrogen for 0.5 hr.8,13-Epoxy-7β-(hydroxyaminocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one (2.0 g) was dissolved in 75 ml ofmethylene chloride and 5 ml of tetrahydrofuran and was added to thereaction mixture. The reaction mixture was stirred under nitrogen for 3hrs. The solution was concentrated to a final volume of 15 ml and flashchromatographed on silica gel. The column was eluted with 1:1hexane:ethyl acetate. The appropriate fractions were combined and thesolvent was removed. Recrystallization from hexane/ethyl acetate gave380 mg (16%) of product, mp 200°-203°.

ANALYSIS: Calculated for C₂₆ H₃₉ NO₁₀ : 59.41% C, 7.49% H, 2.66% N.Found: 59.41% C, 7.43% H, 2.68% N.

EXAMPLE 348,13-Epoxy-7β-[N-2,2-(dimethylpropionyloxy)aminocarbonyloxy]-1α,6β,9α-trihydroxylabd-14-en-11-one

Pivalic acid (143 mg) dissolved in 10 ml of dichloromethane was stirredwith 228 mg of 1,1'-carbonyldiimidazole dissolved in 40 ml ofdichloromethane under nitrogen for 20 min at ambient temperature.8,13-Epoxy-7β-(N-hydroxyaminocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one(500 mg) dissolved in 55 ml of 10:1 tetrahydrofuran in dichloromethanewas added, and the resultant mixture was stirred overnight. The mixturewas evaporated to a final volume of 20 ml and flash chromatographed onsilica gel in 3:1 hexane:ethyl acetate. The appropriate fractions werecombined and evaporated. The residue was crystallized from hexane:etherto give 238 mg (38.8%) of product, mp 105°-108°.

ANALYSIS: Calculated for C₂₆ H₄₁ NO₉ : 61.03% C, 8.09% H, 2.74% N.Found: 61.47% C, 8.39% H, 2.91% N.

EXAMPLE 358,13-Epoxy-7β-(N-propylaminocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one

8,13-Epoxy-7β-(N-propylaminocarbonyloxy)-1α,6β,9α-labd-14-en-11-one-1,9-dimethylformamideacetal (657.4 mg) was dissolved in 21 ml of methanol and 7 ml of water.The mixture was stirred under nitrogen at 60° for 5 days. The mixturewas evaporated. The residue was partitioned between ethyl acetate and 1Nhydrochloric acid. The organic phase was separated and washed with 1Nhydrochloric acid, water, saturated sodium bicarbonate solution andsaturated sodium chloride solution. The ethyl acetate solution was driedover anhydrous sodium sulfate, filtered and evaporated. The residue wasdissolved in methanol and the solution was poured into water withvigorous stirring. The precipitate was collected and vacuum dried at100° to provide 337 mg (57.6%) of product, mp 120°-123°.

ANALYSIS: Calculated for C₂₄ H₃₉ NO₇ : 63.54% C, 8.68% H, 3.09% N.Found: 63.45% C, 8.65% H, 2.97% N.

EXAMPLE 368,13-Epoxy-7β-(N-acetoxyaminocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one

To a stirred solution of 250 mg of acetic acid in 50 ml of methylenechloride was added 680 mg of 1,1'-carbonyldiimidazole. The mixture wasstirred for 45 mins under a nitrogen atmosphere.8,13-Epoxy-7β-(N-hydroxyaminocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one(1.5 g) dissolved in 50 ml of methylene chloride and 10 ml oftetrahydrofuran was added, and the reaction mixture was stirred under anitrogen atmosphere for 48 hrs. The solution was concentrated to a finalvolume of 15 ml and the residue was flash chromatographed on silica gel.The column was eluted with 1:1 hexane:ethyl acetate. The appropriatefractions were combined, the solvent was removed, and the residue wascrystallized from hexane:ethyl acetate to give 680 mg (42%) of product,98°-103°.

ANALYSIS: Calculated for C₂₃ H₃₅ NO₉ : 58.82% C, 7.53% H, 2.98% N.Found: 58.59% C, 7.52% H, 3.33% N.

EXAMPLE 378,13-Epoxy-7β-(N-propionyloxyaminocarbonyloxy)-1α,6β,9.alpha.-trihydroxylabd-14-en-11-one

To a stirred solution of 250 mg of propionic acid in 50 ml of methylenechloride was added 540 mg of 1,1'-carbonyldiimidazole. The mixture wasstirred under a nitrogen atmosphere for 1 hr at room temperature. Asolution of 1.2 g of8,13-epoxy-7β-(N-hydroxyaminocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-onein 50 ml of methylene chloride and 10 ml of tetrahydrofuran was addedand the reaction mixture was stirred for 48 hrs. The solution wasconcentrated and the residue was flash chromatographed on silica gel.The column was eluted with 1:1 hexane:ethyl acetate. The appropriatefractions were combined and the solvent was removed. The residue wascrystallized from hexane:ether to give 710 mg (53%) of product, mp110°-114°.

ANALYSIS: Calculated for C₂₄ H₃₇ NO₉ : 59.61% C, 7.71% H, 2.90% N.Found: 59.24% C, 7.67% H, 3.10% N.

EXAMPLE 388,13-Epoxy-7β-[N-(2-methylpropionyloxy)aminocarbonyloxy]-1α,6.beta.,9α-trihydroxylabd-14-en-11-one

To a stirred solution of 300 mg of isobutyric acid in 50 ml of methylenechloride was added 540 mg of 1,1'-carbonyldiimidazole and the resultingmixture was stirred at room temperature under a nitrogen atmosphere for1 hr.8,13-Epoxy-7β-(N-hydroxyaminocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one(1.2 g) dissolved in 10 ml of tetrahydrofuran and 50 ml of methylenechloride was added dropwise, and the mixture was allowed to stirovernight. The solution was concentrated and the residue waschromatographed on silica gel. The column was eluted with hexane:ethylacetate (2:1). The appropriate fractions were collected and the solventwas removed under reduced pressure to give 1.02 g (71%) of product, mp100°-110°.

ANALYSIS: Calculated for C₂₅ H₃₁ NO₉ : 60.33% C, 7.91% H, 2.81% N.Found: 60.01% C, 8.20% H, 3.10% N.

EXAMPLE 398,13-Epoxy-7β-[N-(1-methylpiperidin-4-yl-carbonyloxy)aminocarbonyloxy]-1α,6β,9α-trihydroxylabd-14-en-11-onehydrochloride hydrate

To a stirred solution of 503 mg 1-methylpiperidin-4-yl-carboxylic acidhydrochloride in 50 ml of methylene chloride was added 282 mg oftriethylamine. The mixture was stirred at 0° for 15 mins and then 455 mgof 1,1'-carbonyldiimidazole was added. The reaction mixture was stirredfor 45 mins at room temperature under a nitrogen atmosphere.8,13-Epoxy-7β-(N-hydroxyaminocarbonyloxy)-1α,6β,9α-labd-14-en-11-one(1.0 g) dissolved in 5 ml of tetrahydrofuran and 50 ml of methylenechloride was added and the mixture was stirred overnight at roomtemperature. The reaction mixture was washed with water, 0.01Nhydrochloric acid and saturated sodium bicarbonate solution, dried overanhydrous sodium sulfate, filtered, and the solvent was removed underreduced pressure. A sample (600 mg) of the residue (1.2 g) was dissolvedin ether and ethereal hydrogen chloride was added until the pH remainedslightly acidic. The product was collected and dried under vacuum togive 370 mg (56%) of product, mp 168° (dec).

ANALYSIS: Calculated for C₂₈ H₄₇ ClN₂ O₁₀ : 55.38% C, 7.82% H, 4.61% N.Found: 55.19% C, 7.44% H, 4.81% N.

EXAMPLE 408,13-Epoxy-7β-[N-(3-hydroxypropyl)aminocarbonyloxy]-1α,6β,9α-trihydroxylabd-11-en-14-one

A stirred solution of 1.8 g8,13-epoxy-7β-[N-(3-hydroxypropyl)aminocarbonyloxy]-1α,6β,9α-trihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal in 50 ml of methanol and 16 ml of water was heated at 60° for 72hrs. The reaction mixture was allowed to cool to room temperature, water(20 ml) was added and the mixture was extracted with methylene chloride.The methylene chloride layer was dried over anhydrous sodium sulfate,filtered, and the solvent was removed. The residue was chromatographedon silica gel. The column was eluted with hexane:ethyl acetate:methanol(1:1:0.1). The appropriate fractions were collected and the solvent wasremoved to give 1.3 g (81%) of product, mp 188°.

ANALYSIS: Calculated for C₂₄ H₃₉ NO₈ : 61.37% C, 8.39% H, 2.98% N.Found: 61.39% C, 8.43% H, 2.94% N.

EXAMPLE 418,13-Epoxy-7β-[(N-propionyloxy-N-methyl)aminocarbonyloxy]-1α,6.beta.,9α-trihydroxylabd-14-en-11-one

To a stirred solution of 164 mg of propionic acid in 50 ml of methylenechloride was added 360 mg of 1,1'-carbonyldiimidazole. The mixture wasstirred at room temperature under a nitrogen atmosphere for 45 mins. Asolution of 1.0 g of8,13-epoxy-7β-(N-methyl-N-hydroxy)aminocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-onein 10 ml of tetrahydrofuran and 50 ml of methylene chloride was addedand the mixture was stirred for 16 hrs. The reaction mixture wasconcentrated and the residue was chromatographed on silica gel. Thecolumn was eluted with hexane:ethyl acetate (3:2). The appropriatefractions were collected and the solvent was removed under reducedpressure to give 660 mg (59.8%) of product, mp 194°.

ANALYSIS: Calculated for C₂₅ H₃₉ NO₉ : 60.33% C, 7.91% H, 2.81% N.Found: 60.46% C, 7.87% H, 2.68% N.

EXAMPLE 428,13-Epoxy-7β-[N-(2-oxopropyl)aminocarbonyloxy]-1α,6β,9.alpha.-trihydroxylabd-14-en-11-one

8,13-Epoxy-7β-[(N-2-oxopropyl)aminocarbonyloxy]-1α,6β,9.alpha.-trihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal (1.7 g) was dissolved in 50 ml of methanol and 20 ml of water.The mixture was heated in an oil bath at 60° for 72 hrs. The reactionmixture was cooled to room temperature and extracted with methylenechloride. The methylene chloride extracts were dried over anhydroussodium sulfate and the solvent was removed. The residue waschromatographed on silica gel. The column was eluted with 1:1hexane:ethyl acetate. The appropriate fractions were collected and thesolvent was removed to give 1.04 g (69.7%) of product, mp 192°.

ANALYSIS: Calculated for C₂₄ H₃₇ NO₈ : 61.64% C, 7.99% H, 2.99% N.Found: 61.70% C, 7.96% H, 2.87% N.

EXAMPLE 437β-(N-Cyclopropylcarbonyloxyaminocarbonyloxy)-1α,6β,9.alpha.-trihydroxylabd-14-en-11-one

To a stirred solution of 241 mg of cyclopropanecarboxylic acid in 50 mlof methylene chloride was added 454 mg of 1,1'-carbonyldiimidazole. Themixture was stirred for 1 hr, and 1.0 g of8,13-epoxy-7β-(hydroxylaminocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-onedissolved in 50 ml of methylene chloride and 10 ml of tetrahydrofuranwas added. The reaction mixture was stirred for 16 hrs at roomtemperature under a nitrogen atmosphere. The mixture was concentratedand the residue was chromatographed on silica gel. The column was elutedwith hexane:ethyl acetate (2:1). The appropriate fractions werecollected and the solvent removed to give 870 mg of product, mp 198°.

ANALYSIS: Calculated for C₂₅ H₃₇ NO₉ : 60.58% C, 7.54% H, 2.83% N.Found: 60.57% C, 7.56% H, 2.77% N.

EXAMPLE 448,13-Epoxy-7β-[N-(2-methoxy-2-methylpropionyloxy)aminocarbonyloxy]-1.alpha.,6β,9α-trihydroxylabd-14-en-11-one

To a stirred solution of 330 mg of 2-methoxyisobutyric acid and 50 ml ofmethylene chloride was added 454 mg of 1,1'-carbonyldiimidazole. Themixture was stirred at room temperature for 1 hr and then 1.0 g8,13-epoxy-7β-(hydroxylaminocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-onedissolved in 50 ml of methylene chloride and 10 ml tetrahydrofuran wasadded. The mixture was stirred overnight at room temperature under anitrogen atmosphere and was concentrated under reduced pressure. Theresidue was chromatographed on silica gel. The column was eluted withhexane:ethyl acetate (1:1). The appropriate fractions were collected andthe solvent was removed. The residue was crystallized from hexane:ethylacetate to give 1.01 g (83%) of product, mp 178°.

ANALYSIS: Calculated for C₂₆ H₄₁ NO₁₀ : 59.17% C, 7.84% H, 2.65% N.Found: 59.15% C, 7.80% H, 2.50% N.

EXAMPLE 457β-[N-(3,3-Dimethylacryloyloxy)aminocarbonyloxy]-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one

To a stirred suspension of 1.0 g of8,13-epoxy-7β-(hydroxyaminocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-oneand 280 mg of 3,3-dimethylacrylic acid in 100 ml of methylene chloridewas added 530 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride followed by 340 mg of 4-dimethylaminopyridine. The mixturewas stirred for 1 hr under an atmosphere of nitrogen and then washedwith 0.01N hydrochloric acid, saturated sodium bicarbonate solution andwater. The organic layer was separated, dried over anhydrous sodiumsulfate and filtered. The solvent was removed under reduced pressure andthe residue was chromatographed on silica gel. The column was elutedwith hexane:ethyl acetate (3:2). The appropriate fractions werecollected and the solvent was removed to give 0.52 g of product, mp105°-110°.

ANALYSIS: Calculated for C₂₆ H₃₉ NO₉ : 61.27% C, 7.73% H, 2.75% N.Found: 60.95% C, 7.71% H, 2.66% N.

EXAMPLE 468,13-Epoxy-7β-[N-(3-methoxyacetoxy)aminocarbonyloxy]-1α,6β,9α-trihydroxylabd-14-en-11-one

To a stirred suspension of 1.0 g of8,13-epoxy-7β-(hydroxylaminocarbonyloxy)-1α,6β,9α-trihydroxylabad-14-en-11-oneand 252 mg of methoxyacetic acid in 100 ml of methylene chloride wasadded 530 mg of 1-(3'-dimethylpropyl)-3-ethylcarbodiimide hydrochlorideand 340 mg of 4-dimethylaminopyridine. The mixture was stirred at roomtemperature under an atmosphere of nitrogen for 1 hr. The reactionmixture was washed with water, 0.01N hydrochloric acid and saturatedsodium bicarbonate solution. The methylene chloride layer was separated,dried over anhydrous sodium sulfate, and the solvent was removed. Theresidue was crystallized from hexane:ethyl acetate to give 0.5 g (43%)of product, mp 191°.

ANALYSIS: Calculated for C₂₄ H₃₇ NO₁₀ : 57.69% C, 7.47% H, 2.80% N.Found: 57.59% C, 7.58% H, 2.89% N.

EXAMPLE 476β-(Aminocarbonyloxy)-8,13-epoxy-1α,7β,9α-trihydroxylabd-14-en-11-one

To a stirred solution of 524 mg of7β-(aminocarbonyloxy)-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one in20 ml of t-butanol under nitrogen was added 1.9 g of potassiumt-butoxide. The solution was stirred for 1 hr at room temperature undernitrogen, poured into ice water:ethyl acetate and extracted twice withethyl acetate. The combined organic layers were washed with water,saturated sodium chloride solution, dried over anhydrous sodium sulfate,and filtered. The filtrate was evaporated. The residue was purified byflash chromatography on silica gel eluting with 60% ethylacetate:hexanes followed by 75% ethyl acetate:hexanes. The appropriatefractions were combined to provide, after crystallization from ethylacetate:hexanes, 0.076 g (14.6%) of product, mp 225-227.

ANALYSIS: Calculated for C₂₁ H₃₃ NO₇ : 61.29% C, 8.08% H, 3.40% N.Found: 61.25% C, 8.13% H, 3.14% N.

EXAMPLE 487β-[N-(1-Oxo-3-butenyl)oxyaminocarbonyloxy]-8,13-epoxy-1α,6.beta.,9α-trihydroxylabd-14-en-11-one

To a stirred solution of 1.81 mg of 3-butenoic acid in 35 ml ofmethylene chloride was added 340 mg of 1,1'-carbonyldiimidazole. Themixture was stirred at room temperature under a nitrogen atmosphere for45 mins and then a solution of 750 mg of8,13-epoxy-7β-(hydroxylaminocarbonyloxy)1α,6β,9α-trihydroxylabd-14-en-11-onein 40 ml of methylene chloride and 5 ml of tetrahydrofuran was added.The mixture was stirred overnight at room temperature under anatmosphere of nitrogen and then concentrated at reduced pressure. Theresidue was chromatographed on silica gel. The column was eluted withhexane:ethyl acetate (1:1). The appropriate fractions were collected andthe solvent removed to give 245 mg (28%) of product, mp 93°-98°.

ANALYSIS: Calculated for C₂₅ H₃₇ NO₉ : 60.57% C, 7.57% H, 2.82% N.Found: 60.87% C, 7.52% H, 2.60% N.

EXAMPLE 497β-(N-Acryloyloxyaminocarbonyloxy)-8,11-epoxy-1α,6β,9.alpha.-trihydroxylabd-14-en-11-one

To a stirred solution of 200 mg of acrylic acid in 50 ml of methylenechloride at 0° was added 283 mg of triethylamine followed by 332 mg oftrimethylacetyl chloride. The mixture was stirred at 0° under a nitrogenatmosphere for 45 mins. A solution of 1.0 g of8,13-epoxy-7β-(hydroxylaminocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-oneand 34 mg of 4-dimethylaminopyridine in 50 ml of methylene chloride and10 ml of tetrahydrofuran was added to the cold reaction mixture. Themixture was stirred at 0° for 0.5 hr. The reaction mixture was washedwith water, 0.01N hydrochloric acid and saturated sodium bicarbonatesolution, dried over anhydrous sodium sulfate and filtered. The solventwas removed and the residue was chromatographed on silica gel. Thecolumn was eluted with hexane:ethyl acetate (1:1). The appropriatefractions were collected and the solvent removed to give 0.4 g (36%) ofproduct, mp 115°-120° .

ANALYSIS: Calculated for C₂₄ H₃₅ NO₉ : 59.85% C, 7.34% H, 2.91% N.Found: 59.63% C, 7.34% H, 2.72% N.

EXAMPLE 508,13-Epoxy-6β-(1-pyrrolidinocarbonyloxy)-1α,7β,9α-trihydroxylabd-14-en-11-one

8,13-Epoxy-6β-(1-pyrrolidinocarbonyloxy)-1α,7β,9α-trihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal (2.7 g), was dissolved in 70 ml of methanol and 20 ml of water.The mixture was stirred at 55° for 74 hrs. After cooling to roomtemperature, the reaction mixture was diluted with saturated sodiumchloride solution and extracted with ethyl acetate. The ethyl acetateextracts were dried over anhydrous sodium sulfate and the solvent wasremoved under reduced pressure. The residue was chromatographed onsilica gel. The column was eluted with hexane:acetone (2:1). Theappropriate fractions were collected and the solvent was removed to give1.2 g (50%) of product, mp 135°-140°.

ANALYSIS: Calculated for C₂₅ H₃₉ NO₇ : 64.48% C, 8.46% H, 3.01% N.Found: 64.35% C, 8.49% H, 2.90% N.

EXAMPLE 518,13-Epoxy-6β-[N-(2-hydroxyethyl)aminocarbonyloxy]-1α,7β,9.alpha.-trihydroxylabd-14-en-11-one

8,13-Epoxy-6β-[N-(2-hydroxyethyl)aminocarbonyloxy]-1α,7β,9.alpha.-trihydroxylabad-14-en-11-one-1,9-dimethylformamideacetal (1.1 g) was dissolved in 30 ml of methanol and 10 ml of water.The mixture was stirred at 55° for 72 hrs. After cooling to roomtemperature, the reaction mixture was diluted with saturated sodiumchloride solution and extracted with ethyl acetate. The ethyl acetateextracts were dried over anhydrous sodium sulfate, filtered, and thesolvent was removed under reduced pressure. The residue waschromatographed on silica gel. The column was eluted with hexane:acetone(1:1). The appropriate fractions were collected and the solvent wasremoved to give 0.63 mg (62%) of product as an amorphous solid, mp125°-140°.

ANALYSIS: Calculated for C₂₃ H₃₇ NO₈ : 60.63% C, 8.20% H, 3.08% N.Found: 60.44% C, 8.08% H, 2.94% N.

EXAMPLE 526β-(N,N-Dimethylaminocarbonyloxy)-1α,7β,9α-trihydroxylabd-14-en-11-one

To a stirred solution of 1.5 g of8,13-epoxy-7β-(N,N-dimethylaminocarbonyloxy)-1α,6β,9.alpha.-trihydroxylabd-14-en-11-onein 50 ml of t-butanol and 5 ml of tetrahydrofuran at 0° was added 5.3 gof potassium t-butoxide. The mixture was stirred under a nitrogenatmosphere at 0° for 20 mins. The ice/water bath was removed and thereaction mixture was stirred an additional 4 hrs at room temperature.The reaction mixture was poured into an ice/water mixture and extractedwith ethyl acetate. The ethyl acetate extracts were washed with water,saturated sodium chloride solution, dried over anhydrous sodium sulfate,and filtered. The filtrate was evaporated. The residue was flashchromatographed on silica gel. The column was eluted with 1:1 ethylacetate:hexane followed by 2;1 ethyl acetate:hexane. The appropriatefractions were combined, the solvent was removed and the residue wascrystallized from hexane:ethyl acetate to give 870 mg (51.3%) ofproduct, mp 212°-215°.

ANALYSIS: Calculated for C₂₃ H₃₇ NO₇ : 62.84% C, 8.50% H, 3.18% N.Found: 62.53% C, 8.35% H, 3.31% N.

EXAMPLE 538,13-Epoxy-7β-(N-ethoxylaminocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one

8,13-Epoxy-7β-(N-ethoxylaminocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal (2.0 g) was dissolved in 50 ml of methanol and 16 ml of distilledwater. The solution was heated at 60° for 72 hrs. After cooling to roomtemperature, the mixture was diluted with 20 ml saturated sodiumchloride solution and extracted with ethyl acetate. The ethyl acetateextracts were dried over anhydrous sodium sulfate, filtered, and thesolvent was removed. The residue was chromatographed on silica gel. Theappropriate fractions were combined and the solvent was removed.Crystallization from hexane:ether gave 900 mg (50.6%) of product, mp105°.

ANALYSIS: Calculated for C₂₃ H₃₇ NO₈ : 60.63% C, 8.20% H, 3.08% N.Found: 60.79% C, 8.63% H, 3.33% N.

EXAMPLE 548,13-Epoxy-7β-(N-propylaminocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal

8,13-Epoxy-1α,6β,7β,9α-tetrahydroxylabd-14-en-11-one-1,9-dimethylformamideacetal (1.0 g) was dissolved in 100 ml of tetrahydrofuran and 230 ul ofa 1M solution of lithium bis(trimethylsilyl)amide at ambient temperatureunder nitrogen. The mixture was allowed to equilibrate for 15 min.Propyl isocyanate (435 ul, 391.5 mg) was added after which the mixturewas stirred at 50° for 1 hr. The reaction mixture was quenched with 1 mlof water and evaporated. The residue was partitioned between ether andsaturated aqueous sodium bicarbonate solution. The ether layer wasevaporated. The residue was flash chromatographed on silica gel inhexane:ethyl acetate (3:1). The appropriate fractions were combined andevaporated. The residue was dissolved in ether and evaporated severaltimes to provide a foam which was then vacuum dried at 60° to give 694mg (59.4%) of product, mp 83°-90°.

ANALYSIS: Calculated for C₂₇ H₄₄ N₂ O₇ : 63.74% C, 8.74% H, 5.50% N.Found: 63.63% C, 8.68% H, 5.35% N.

EXAMPLE 558,13-Epoxy-7β-(N-ethoxyaminocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal

To a stirred solution of 5.0 g of8,13-epoxy-1α,6β,7β,9α-tetrahydroxylabd-14-en-11-one-1,9-dimethylformamideacetal in 100 ml of methylene chloride was added 2.3 g of1,1'-carbonyldiimidazole. The solution was stirred at room temperatureovernight under a nitrogen atmosphere. A solution ofO-ethylhydroxylamine was prepared by dissolving 2.9 g of O-ethylhydroxylamine hydrochloride in 33 ml of methanol and phenolthalien as anindicator. A 25% sodium methoxide in methanol solution (7.0 ml) wasadded until the color remained light pink. The O-ethylhydroxylaminesolution was added to the reaction mixture. After four days, the mixturewas diluted with 100 ml methylene chloride washed with 0.01Nhydrochloric acid, saturated sodium bicarbonate solution and water. Theorganic layer was separated, dried over sodium sulfate, filtered, andthe solvents were removed. The residue was chromatographed on silicagel, eluting with hexane:ethyl acetate (1:1). The appropriate fractionswere collected and the solvent was removed to give 3.0 g (50%) ofproduct, as a foam, mp 90°-95°.

ANALYSIS: Calculated for C₂₆ H₄₂ N₂ O₈ : 61.14% C, 8.31% H, 5.48% N.Found: 60.87% C, 8.20% H, 5.57% N.

EXAMPLE 568,13-Epoxy-6β-[N-(2-hydroxyethyl)aminocarbonyloxy]-1α,7β,9.alpha.-trihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal

To a stirred solution of 300 mg of8,13-epoxy-1α,6β,7β,9α-tetrahydroxylabd-14-en-11-one-1,9-dimethylformamideacetal in 6 ml of methylene chloride was added 140 mg of1,1'-carbonyldiimidazole followed by 0.2 ml of triethylamine. Themixture was stirred 24 hrs at room temperature under an atmosphere ofnitrogen. Ethanolamine (200 mg) was added and the mixture was stirred anadditional 16 hrs. The mixture was diluted with 10 ml of methylenechloride and washed with 0.01N hydrochloric acid until the washings wereneutral. The organic portion was dried over anhydrous sodium sulfate andthe solvent was removed. The residue was chromatographed on silica gel.The column was eluted with hexane:ethyl acetate:methanol (1:1:0.1). Theappropriate fractions were collected and the solvent was removed to give240 mg (66%) of product, mp 116°-120°.

ANALYSIS: Calculated for C₂₆ H₄₂ N₂ O₈ : 61.14% C, 8.31% H, 5.48% N.Found: 60.91% C, 8.35% H, 5.33% N.

EXAMPLE 578,13-Epoxy-6β-(1-pyrrolidinocarbonyloxy)-1α,7β,9α-trihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal

8,13-Epoxy-1α,6β,7β,9α-tetrahydroxylabd-14-en-11-one-1,9-dimethylformamideacetal (3.0 g) was dissolved in 60 ml of methylene chloride and 1.38 gof 1,1'-carbonyldiimidazole was added followed by 1.65 g oftriethylamine. After stirring for 24 hrs at room temperature,pyrrolidine (2.5 g) was added and the mixture was stirred for 48 hrs.The reaction mixture was diluted with 50 ml of methylene chloride andextracted repeatedly with 0.01N hydrochloric acid until the washing wereacidic. The organic layer was dried over anhydrous sodium sulfate,filtered and the solvent was removed. The residue was chromatographed onsilica gel. The column was eluted with 2:1 hexane:acetone. Theappropriate fractions were collected and the solvent was removed to give3.06 g (82%) of product as an amorphous solid.

ANALYSIS: Calculated for C₂₈ H₄₄ N₂ O₇ : 64.58% C, 8.53% H, 5.38% N.Found: 64.22% C, 8.35% H, 5.34% N.

EXAMPLE 588,13-Epoxy-7β-(N-methyl-N-propionylaminocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal

To a stirred solution of 4.0 g of8,13-epoxy-1α,6β,7β,9α-tetrahydroxylabd-14-en-11-one-1,9-dimethylformamideacetal in 80 ml of tetrahydrofuran at 0° was added 11.2 ml of a 1Msolution in THF of lithium bis(trimethylsilyl)amide. The mixture wasstirred at 0° for 45 mins and 2.95 g of N-methyl-N-propionylcarbamoylchloride was added. The reaction mixture was slowly warmed to refluxtemperature and was refluxed for 16 hrs. After cooling to roomtemperature, the mixture was diluted with 200 ml of methylene chlorideand washed with water. The organic phase was dried over anhydrous sodiumsulfate, filtered, and the solvent was removed. The residue waschromatographed on silica gel. The column was eluted with 1:1hexane:ethyl acetate. The appropriate fractions were collected and thesolvent was removed to give 3.02 g (59.9%) of product as an oil.

ANALYSIS: Calculated for C₂₈ H₄₄ N₂ O₈ : 62.65% C, 8.28% H, 5.22% N.Found: 62.44% C, 8.65% H, 5.15% N.

EXAMPLE 598,13-Epoxy-7β-[N-(3-hydroxypropyl)aminocarbonyloxy]-1α,6β,9α-labd-14-en-11-one-1,9-dimethylformamideacetal

To a stirred solution of 3.0 g of8,13-epoxy-1α,6β,7β,9α-tetrahydroxylabd-14-en-11-one-1,9-dimethylformamideacetal in 60 ml of methylene chloride was added 1.38 g of1,1'-carbonyldiimidazole. The mixture was stirred under a nitrogenatmosphere at room temperature for 16 hrs. 3-Aminopropanol (2.64 g)dissolved in 10 ml of methylene chloride was added to the reactionmixture, and the mixture was stirred for 18 hrs at room temperature. Thereaction mixture was diluted with 50 ml of methylene chloride and washedwith 0.01N hydrochloric acid until the washings remained acidic. Themethylene chloride layer was dried over anhydrous sodium sulfate,filtered, and the filtrate was concentrated. The residue waschromatographed on silica gel. The column was eluted with hexane:ethylacetate:methanol (1:1:0.1). The appropriate fractions were collected andthe solvent was removed to give 2.6 g (70%) of product, mp 168°-170°.

ANALYSIS: Calculated for C₂₇ H₄₄ N₂ O₈ : 61.79%C, 8.47%H, 5.34%N. Found:61.94%C, 8.89%H, 5.54%N.

EXAMPLE 608,13-Epoxy-7β-[N-(2-oxopropyl)aminocarbonyloxy]-1α,6β,9.alpha.-trihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal

A solution of 0.6 ml oxalyl chloride in 15 ml of methylene chloride wasstirred under nitrogen in a dry ice acetone bath. A mixture of 1.02 mlof dimethysulfoxide and 3 ml of methylene chloride was added dropwise ata rate such the temperature did not exceed -50°. After stirring for 2mins, 3.0 g of8,13-epoxy-7β-[N-(2-hydroxypropyl)aminocarbonyloxy]-1α,6β,9α-trihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal in 6 ml of methylene chloride was added over a period of 5 mins.The mixture was stirred at -60° for 15 mins. and 4.2 ml of triethylaminewas added. The mixture was allowed to warm to room temperature, dilutedwith 50 ml of methylene chloride and washed with water, 0.01Nhydrochloric acid and saturated sodium bicarbonate solution. The organiclayer was dried over anhydrous sodium sulfate and the solvent wasremoved under reduced pressure. The residue was chromatographed onsilica gel. The column was eluted with hexane:ethyl acetate:methanol(1:1:0.1). The appropriate fractions were collected and the solvent wasremoved to give 2.07 g (69.5%) of product, mp 173° -174°.

ANALYSIS: Calculated for C₂₇ H₄₂ N₂ O₈ : 62.03%C, 8.12%H, 5.36%N. Found:61.98%C, 8.09%H, 5.16%N.

EXAMPLE 617β-(Aminocarbonyloxy)-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one-1,9-carbonate

To a stirred solution of 1.5 g of7β-(aminocarbonyloxy)-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one in50 ml of methylene chloride was added 708 mg of 1,1'-carbonyldimidazolefollowed by 441 mg of triethylamine. The mixture was stirred overnightat room temperature under a nitrogen atmosphere. After 16 hrs, themixture was diluted with 50 ml of methylene chloride, washed with waterand dried over anhydrous sodium sulfate, and filtered. The methylenechloride was evaporated under reduced pressure and the residue waschromatographed on silica gel. The column was eluted with hexane:ethylacetate (1:1). The appropriate fractions were collected and the solventwas removed to give 0.9 g (57.2%) of product, mp 103°.

ANALYSIS: Calculated for C₂₂ H₃₁ NO₈ : 60.39%C, 7.16%H, 3.20%N. Found:60.17%C, 7.17%H, 3.20%N.

EXAMPLE 628,13-Epoxy-7β-(N-propionylaminocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one-1,9-carbonate

7β-(Aminocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one-1,9-carbonate(2.2 g) was dissolved in 10 ml of propionic anhydride and a drop ofconcentrated sulfuric acid was added. The mixture was stirred at roomtemperature under an atmosphere of nitrogen. The mixture was dilutedwith saturated sodium bicarbonate solution and extracted with ether. Theether extracts were dried over anhydrous sodium sulfate, filtered, andthe solvent was removed under vacuum. The residue was chromatographed onsilica gel. The column was eluted with hexane:ethyl acetate (3:1)followed by hexane:ethyl acetate (1:1). The appropriate fractions werecollected and the solvent was removed to give 2.0 g (81%) of product, mp135°.

ANALYSIS: Calculated for C₂₅ H₃₅ NO₉ : 60.83%C, 7.16%H, 2.84%N. Found:60.75%C, 7.23%H, 2.64%N.

EXAMPLE 637β-(Aminocarbonyloxy)-1α-(N-t-butylaminoacetoxy)-6β,9.alpha.-dihydroxy-8,13-epoxylabd-14-en-11-onehydrochloride hydrate

7β-(Aminocarbonyloxy)-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one(250 mg) was dissolved in 3 ml of dichloromethane and 84.8 μl (81.1 mg)of dimethylaniline at 5°. A solution of 64.1 μl (148.4 mg) ofbromoacetyl bromide in 2 ml of dichloromethane was added to the chilledsolution over 15 mins and the solution was stirred for 1 hr at thattemperature. The reaction mixture was warmed to room temperature andpoured into a mixture of ice, water and ethyl acetate. The aqueous layerwas extracted several times with ethyl acetate. The organic extractswere washed with saturated aqueous bicarbonate solution, dried overanhydrous sodium sulfate, filtered, and evaporated. The residue wasdissolved in 2 ml ethyl acetate and the solution was stirred at ambienttemperature under nitrogen. A solution of 129 μl of t-butylamine (178mg) dissolved in 2 ml of ethyl acetate was added, after which themixture was stirred overnight. The reaction mixture was poured intosaturated aqueous sodium bicarbonate solution and extracted with ethylacetate. The combined organic extracts were dried over anhydrous sodiumsulfate, filtered and evaporated. The residue was flash chromatographedon silica gel in hexane:ethyl acetate:methanol (10:10:0.1). Theappropriate fractions were combined and evaporated. The residue wasdissolved in ether, from which the hydrochloride salt was precipitatedby treatment with hydrogen chloride. Filtration afforded 153.4 mg(43.7%) of product, mp 166°-179° (dec).

ANALYSIS: Calculated for C₂₇ H₄₄ N₂ O₈.HCl.H₂ O: 55.99%C, 8.20%H,4.83%N. Found: 55.61%C, 7.95%H, 4.52%N.

EXAMPLE 641α-(N-t-Butylaminoacetoxy)-6β,9α-dihydroxy-7β-[N-(2,2-dimethylpropionyloxy)aminocarbonyloxy]abd-8,13-epoxy-14-en-11-onehydrochloride

To a stirred solution of 2.05 g of8,13-epoxy-7β-[N-(2,2-dimethylpropionyloxy)aminocarbonyloxy]-1α,6β,9α-trihydroxylabd-14-en-11-onein 10 ml of methylene chloride was added 0.52 g of dimethylaniline. Themixture was cooled to 4° and a solution of 0.94 g of bromoacetyl bomidein 10 ml of methylene chloride was added dropwise over a period of 0.5hr. The mixture was stirred a 5° under a nitrogen atmosphere for anadditional hour. After equilibrating to room temperature, the mixturewas poured into 50 ml of saturated sodium bicarbonate solution/ice, andthe mixture was diluted with 50 ml of methylene chloride, washed withsaturated sodium bicarbonate solution and dried over anhydrous sodiumsulfate, and filtered. The solvent was removed and the residue wasdissolved in 20 ml of methylene chloride. A solution of 1.4 g oft-butylamine in 20 ml ethyl acetate was added and the resulting mixturewas stirred overnight under nitrogen. The reaction mixture was dilutedwith methylene chloride, washed with saturated sodium bicarbonatesolution and water and dried over anhydrous sodium sulfate. The solventwas removed and the residue was chromatographed on silica gel. Theappropriate fractions were collected and concentrated. The residue wasdissolved in ether and anhydrous hydrogen chloride was passed throughthe solution to give 375 mg (15%) of product, mp 98°-103°.

ANALYSIS: Calculated for C₃₂ H₅₃ N₂ O₁₀ Cl: 58.12%C, 8.08%H, 4.20%N.Found: 57.77%C, 8.34%H, 4.59%N.

EXAMPLE 651α-(N-t-Butylaminoacetoxy)-6β,9α-dihydroxy-8,13-epoxy-7.beta.-(N-methylaminocarbonyloxy)labd-14-en-11-onehydrchloride hydrate

8,13-Epoxy-7β-(N-methylaminocarbonyloxy)-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one(280 mg) was dissolved in 6 ml of dry dichloromethane and 95 μl (81.8mg) of N,N-dimethylaniline. The mixture was stirred chilled to 5° undernitrogen. A solution of 69 μl (159.5 mg) of bromoacetyl bromide in 2 mlof dry dichloromethane was added over 15 min, after which the mixturewas stirred for 1 hr. The reaction mixture was poured into chilleddilute sodium bicarbonate solution. The product was extracted into ethylacetate, and the solution was dried over anhydrous sodium sulfate,filtered and evaporated. The residue was dissolved in 4 ml of ethylacetate and 140 μl (192.4 mg) of t-butylamine. The mixture was stirredat ambient temperature under nitrogen overnight, after which it wasdiluted with dichloromethane and washed with saturated aqueous sodiumbicarbonate solution and saturated brine. After drying the mixture oversodium sulfate and filtration, the solvent was removed by evaporation.The residue was flash chromatographed on silica gel in hexane:ethylacetate:methanol (10:10:0). The appropriate fractions were combined andevaporated. The residue was dissolved in ether from which thehydrochloride was precipitated by treatment with hydrogen chloride.Filtration afforded 192 mg (54.2%) of product, mp 163°-187° (dec).

ANALYSIS: Calculated for C₂₈ H₄₉ ClNO₉ : 56.69%C, 8.34%H, 4.72%N. Found:56.68%C, 8.10%H, 4.68%N.

EXAMPLE 667β-[N-(N-Acetylglycyloxy)aminocarbonyloxy]-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one

To a stirred solution of 246 mg of N-acetylglycine in 25 ml ofdimethylformamide was added 340 mg of 1,1'-carbonyldiimidazole. Themixture was stirred for 45 mins at room temperature under a nitrogenatmosphere.8,13-Epoxy-7β-(hydroxyaminocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one(750 mg) dissolved in 25 ml of dimethylformamide was added and thereaction mixture was stirred overnight. The mixture was diluted withwater and extracted with methylene chloride. The methylene chlorideextracts were washed repeatedly with water, dried over anhydrous sodiumsulfate and filtered. The solvent was removed and the residue wascrystallized from cyclohexane to give 510 mg (55%) of product, mp 55°.

ANALYSIS: Calculated for C₂₄ H₃₈ N₂ O₁₀ : 57.01%C, 7.29%H, 5.32%N.Found: 57.35%C, 7.57%H, 5.37%M.

EXAMPLE 677β-[N-(4-Dimethylaminobutyryloxy)aminocarbonyloxy]-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-onehydrochloride hydrate

To a stirred suspension of 469 mg of 4-dimethylaminobutyric acidhydrochloride in 25 ml of methylene chloride was added 282 g oftriethylamine, and the mixture was stirred for 0.5 hr at roomtemperature under a nitrogen atmosphere. 1,1'-Carbonyldiimidazole (455mg) was added and the mixture stirred for 45 mins before the addition ofa solution of 1.0 g of8,13-epoxy-7β-(hydroxyaminocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-onein 5 ml of tetrahydrofuran and 25 ml of methylene chloride. Afterstirring 16 hrs, the mixture was washed with water, 0.01N hydrochloricacid and saturated sodium bicarbonate solution, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Theresidue was dissolved in anhydrous ether and ethereal hydrogen chloridewas added until the pH was neutral. The precipitate was filtered anddried to give 710 mg (51.8%) of product, mp 125°-130°.

ANALYSIS: Calculated for C₂₇ H₄₄ N₂ O₉ : 54.47%C, 7.97%H, 4.71%N. Found:54.60%C, 7.96%H, 4.50%N.

EXAMPLE 688,13-Epoxy-7β-[N-(2-piperidinoethyl)aminocarbonyloxy]-1α,6β,9α-trihydroxylabd-14-en-11-onehydrochloride hydrate

A solution of 1.23 g of8,13-epoxy-7β-[N-(2-piperdinoethyl)aminocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one1,9-dimethylformamide acetal in 50 ml of 3/1 methanol/water was stirredat 60°-70° under nitrogen for 40 hr. The solution was allowed to cool toroom temperature and concentrated. The residue was dissolved in aminimum volume of 10% tetrahydrofuran/dichloromethane and flashchromatographed on silica gel (eluent: 10%tetrahydrofuran/dichloromethane, 15% tetrahydrofuran/dichloromethane,20% tetrahydrofuran/dichloromethane and 25%tetrahydrofuran/dichloromethane). The appropriate fractions werecombined and concentrated. The residue was dissolved in anhydrous ether,dried over anhydrous sodium sulfate, filtered. The hydrochloride saltwas precipitated by addition of ethereal hydrogen chloride. The salt wascollected and dried at 80° (2 mm) for 2 hr to give 0.62 g (50.2%) ofproduct, mp 156°-191°.

ANALYSIS: Calculated for C₂₈ H₄₆ N₂ O₇.HCl.H₂ O: 58.27%C, 8.56%H,4.85%N. Found: 58.07%C, 8.63%H, 4.88%N.

EXAMPLE 697β-[N-(2-Dimethylaminoethyl)aminocarbonyloxy]-8,13-epoxy-1α,6.beta.,9α-trihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal

To a stirred solution of 3.0 g of8,13-epoxy-1α,6β,9α-tetrahydroxylabd-14-en-11-one-1,9-dimethylformamideacetal in 60 ml of methylene chloride was added 1.38 g of1,1'-carbonyldiimidazole. The mixture was stirred overnight under anitrogen atmosphere at room temperature. N,N-Dimethylethylenediamine(4.7 ml) was added and the reaction mixture was washed with 0.01Nhydrochloric acid until the washings remain neutral. The organic portionwas dried over anhydrous sodium sulfate, filtered, the solvent removed,and the residue chromatographed on silica gel. The column was elutedwith 10% methanol/methylene chloride. The appropriate fractions werecombined and the solvent removed under reduced pressure. The residue wascrystallized from cyclohexane to give 2.3 g (60%) of product, mp162°-163°.

ANALYSIS: Calculated for C₂₈ H₄₇ N₃ O₇ : 62.53%C, 8.83%H, 7.81%N. Found:62.77%C, 8.87%H, 7.63%N.

EXAMPLE 708,13-Epoxy-7β-[N-(2-piperidinoethyl)aminocarbonyloxy]-1α,6β,9α-trihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal

To a stirred solution of 3.0 g of8,13-epoxy-1α,6β,7β,9α-tetrahydroxylabd-14-en-11-one-1,9-dimethylformamideacetal in 60 ml of ethyl acetate was added 1.38 g of1,1'-carbonyldiimidazole. The solution was stirred overnight at roomtemperature. To the solution was added 1.01 ml (0.909 g) of2-aminoethylpiperidine. The solution was poured into ice/ethylacetate/water, extracted twice with ethyl acetate, twice with water,once with saturated sodium chloride solution, dried over anhydroussodium sulfate, and filtered. The filtrate was evaporated. The residuewas dissolved in 5% methanol/dichloromethane and flash chromatographedon silica gel, eluting with 5% methanol/dichloromethane. The appropriatefractions were combined, concentrated and dried at 110° (2 mm) toprovide 1.48 g (36.1%) of product, as a glass.

ANALYSIS: Calculated for C₃₁ H₅₁ N₃ O₇ : 64.44%C, 8.90%H, 7.27%N. Found:64.14%C, 9.04%H, 7.17%N.

EXAMPLE 718,13-Epoxy-6β-(hydroxylaminocarbonyloxy)-1α,7β,9α-trihydroxylabd-14-en-11-one

To a stirred solution of 2.0 g of8,13-epoxy-7β-(hydroxyaminocarbonyloxy)-1α,7β,9α-trihydroxylabd-14-en-11-onein 75 ml of tertiary-butyl alcohol and 5 ml of tetrahydrofuran at 0° wasadded 7.0 g of potassium tertiary-butoxide. The mixture was stirred at0° for 1 hr and slowly warmed to room temperature. After stirring atroom temperature for 1 hr the reaction mixture was poured into ice/waterand extracted with ethyl acetate. The extracts were combined and driedover anhydrous sodium sulfate, the solvent removed and the residuechromatographed on silica gel. The column was eluted with hexane/ethylacetate (1:1) followed by ethyl acetate. The appropriate fractions werecollected and the solvent removed to give 300 mg of product, mp155°-160°.

ANALYSIS: Calculated for C₂₁ H₃₃ NO₈ : 58.99%C, 7.80%H, 3.27%N. Found:58.52%C, 8.05%H, 3.12%N.

EXAMPLE 728,-13-Epoxy-7β-[1-(methylpiperazin-4-yl)carbonyloxy]-1α,6β,9α-trihydroxylabd-14-en-11-one

To a stirred solution of 5.0 g of8,13-epoxy-1α,6β,7β,9α-tetrahydroxylabd-14-en-11-one-1,9-dimethylformamideacetal in 100 ml of dichloromethane was added 2.15 g of1,1'-carbonyldiimidazole. The solution was stirred under nitrogen for 20hr. To the solution was added 1.3 g of 1-methylpiperazine. The solutionwas stirred under nitrogen for 72 hr. The solution was poured intowater/ice/ethyl acetate, extracted twice with ethyl acetate, washed withwater and saturated sodium chloride solution. The ethereal solution wasdried over anhydrous sodium sulfate, filtered and concentrated. Theresidue was dissolved in ethyl acetate and flash chromatographed onsilica gel, eluting with ethyl acetate followed by 30%tetrahydrofuran/ethyl acetate. The appropriate fractions were combinedand concentrated. Recrystallization from hexanes provided 1.81 g ofproduct, mp 209°-215°.

ANALYSIS: Calculated for C₂₉ H₄₇ N₃ O₇ : 63.36%C, 8.62%H, 7.65%N. Found:63.52%C, 8.64%H, 7.56%N.

EXAMPLE 738,13-Epoxy-7β-[N-2-(pyridin-2-ylethyl)aminocarbonyloxy]-1α,6.beta.,9α-trihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal

To 5.05 g of8,13-epoxy-1α,6β,7β,9α-tetrahydrolabd-14-en-11-one-1,9-dimethylformamideacetal was added 100 ml of dry dichloromethane under nitrogen. To thesolution was added 2.17 g of 1,1'-carbonyldiimidazole and the solutionwas stirred for 18 hrs, after which 1.6 ml of 2(2-aminoethyl)pyridinewas added, and the reaction mixture was stirred for 18 hrs. The reactionmixture was poured into ice/water/ether, extracted with ether, washedwith water and saturated sodium chloride solution, dried over anhydroussodium sulfate, filtered and concentrated. The residue was flashchromatographed, employing 50% ethyl acetate/hexane. The appropriatefractions were combined and again flash chromatographed using 25%acetone/hexane to provide 2.80 g (42%) of product, mp 159°.

ANALYSIS: Calculated for C₃₁ H₄₄ N₃ O₇ : 65.12%C, 7.93%H, 7.35%N. Found:65.22%C, 7.90%H, 7.30%N.

EXAMPLE 747β-[N-3-(Dimethylaminopropyl)aminocarbonyloxy]-1α,6β,9.alpha.-trihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal

To a stirred solution of 3.0 g of1α,6β,7β,9α-tetrahydroxylabd-14-en-111,9-dimethylformamide acetal in 60ml of methylene chloride was added 1.38 g of 1,1'-carbonyldiimidazoleand the mixture was stirred overnight under a nitrogen atmosphere atroom temperature. 3-Dimethylaminopropylamine (3.6 g) was added and themixture was stirred an additional 24 hrs. The reaction mixture waswashed with 0.01N hydrochloric acid until the washings remained acidic.The organic layer was dried over anhydrous sodium sulfate, filtered andthe solvent was evaporated. The residue was purified by flashchromatography. The column was eluted with 10% methanol/methylenechloride. The appropriate fractions were collected, the solvent wasevaporated and the residue was crystallized from cyclohexane to give2.75 g (70%) of product, mp 160°.

ANALYSIS: Calculated for C₂₉ H₄₉ N₃ O₇ : 63.12%C, 8.97%H, 7.62%N. Found:62.47%C, 8.93%H, 7.45%N.

EXAMPLE 758,13-Epoxy-7β-[N-2-(pyridylmethyl)aminocarbonyloxy]-1α,7β,9α-trihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal

To 5.00 g of8,13-epoxy-1α,6β,7β,9α-tetrahydroxylabd-14-en-11-one-1,9-dimethylformamideacetal was added 100 ml of dry dichloromethane under nitrogen. To thesolution was added 2.15 g of 1,1'-carbonyldiimidazole and the solutionwas stirred for 18 hrs. To the solution was added 1.37 ml of2-(aminomethyl)pyridine and the solution was stirred for an additional48 hrs. The solution was then poured into ice/water/ethyl acetate,extracted with ether, washed with water and saturated sodium chloride,dried with anhydrous sodium sulfate, filtered and concentrated. Theresidue was flash chromatographed employing 50% ethyl acetate/hexane.The appropriate fractions were combined and again flash chromatographed,employing 25% acetone/hexane to provide 5.46 g (83%) of product.Recrystallization from ether/hexane provided the analytical product, mp113°-114°.

ANALYSIS: Calculated for C₃₀ H₄₃ N₃ O₇ : 64.61%C, 7.77%H, 7.53%N. Found:64.495C, 7.825H, 7.30%N.

EXAMPLE 766β-[N-(3-Dimethylaminopropyl)aminocarbonyloxy]-1α,7β,9.alpha.-trihydroxylabd-14-en-11-one-1,9-dimethylformamide

To a stirred solution of 2.5 g of8,13-epoxy-1α,6β,7β,9α-tetrahydroxylabd-14-en-11-one-6,7-carbonate-1,9-dimethylformamideacetal in 10 ml of methylene chloride was added 8.2 g of3-dimethylaminopropylamine. The mixture was stirred at room temperaturefor 48 hrs. The mixture was diluted with methylene chloride andextracted with 0.01N hydrochloric acid until the extracts were neutral.The methylene chloride layer was dried over anhydrous sodium sulfate,filtered and the solvent was evaporated under reduced pressure. Theresidue was purified by flash chromatography. The column was eluted 10%methanol/methylene chloride. The appropriate fractions were isolated andthe solvent evaporated to give 1.7 g (55.4%) of product, mp 130°-132°.

ANALYSIS: Calculated for C₂₉ H₄₉ N₃ O₇ : 63.12%C, 8.97%H, 7.62%N. Found:63.21%C, 9.04%H, 7.54%N.

EXAMPLE 778,13-Epoxy-6β-(4-methylpiperazinyl)carbonyoxy-1α,7β,9.alpha.-trihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal

To a stirred solution of 3.0 g of8,13-epoxy-1α,6β,7β,9α-tetrahydroxylabd-14-en-11-one-6,7-carbonate-1,9-dimethyformamideacetal in 5 ml of methylene chloride was added 15 ml of1-methylpiperazine. The mixture was stirred 16 hrs under a nitrogenatmosphere. The mixture was diluted with methylene chloride andextracted with 0.01N hydrochloride acid until the washings were neutral.The organic layer was dried over anhydrous sodium sulfate, filtered andthe solvent was evaporated. The residue was chromatographed on silicagel, eluting with 10% methanol/dichloromethane. The appropriatefractions were collected and the solvent was evaporated to give 2.56 g(70.5%) of product.

ANALYSIS: Calculated for C₂₉ H₄₇ N₃ O₇ : 63.35%C, 8.63%H, 7.64%N. Found:63.46%C, 8.66%H, 7.70%N.

EXAMPLE 788,13-Epoxy-6β-(4-pyridylmethyl)aminocarbonyloxy-1α,7β,9.alpha.-trihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal

To a stirred solution of 2.5 g of8,13-epoxy-1α,6β,7β,9α-tetrahydroxylabd-14-en-11-one-6,7-carbonate-1,9-dimethylformamideacetal in 10 ml of methylene chloride was added 5 ml of4-(aminomethyl)pyridine. The mixture was diluted with methylene chlorideand extracted with 0.01N hydrochloric acid until the washings wereacidic. The organic layer was dried over anhydrous sodium sulfate,filtered and the solvent was evaporated. The residue was flashchromatographed on silica gel, eluting with 10%methanol/dichloromethane. The appropriate fractions were collected andthe solvent evaporated to give 1.7 g (55%) of product, mp 145°-147°.

ANALYSIS: Calculated for C₃₀ H₄₃ N₃ O₇ : 64.60%C, 7.78%H, 7.53%N. Found:64.51%C, 7.81%H, 7.43%N.

EXAMPLE 798,13-Epoxy-6β-[N-2-(pyridylmethyl)aminocarbonyloxy]-1α,7β,9α-trihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal

To a stirred solution of 2.5 g of8,13-epoxy-1α,6β,7β,9α-tetrahydroxylabd-14-en-11-one-6,7-carbonate-1,9-dimethylformamideacetal in 10 ml of methylene chloride was added 5 ml of2-(aminomethyl)pyridine. The mixture was stirred for 73 hrs at roomtemperature. The reaction mixture was repeatedly extracted with 0.01Nhydrochloric acid until the washings became acidic. The organic phasewas dried over anhydrous sodium sulfate, filtered and the solvent wasevaporated. The residue was chromatographed on silica gel. The columnwas eluted with 10% methanol/dichloromethane. The appropriate fractionswere collected and the solvent was evaporated to give 1.9 g (60.9%) ofproduct, mp 90°-93°.

ANALYSIS: Calculated for C₃₀ H₄₃ N₃ O₇ : 64.60%C, 7.78%H, 7.53%N. Found:64.61%C, 7.77%N, 7.55%N.

EXAMPLE 808,13-Epoxy-7β-[N-2-(pyridylmethyl)aminocarbonyloxy]-1α,6β,9α-trihydroxylabd-14-en-11-onehydrochloride hydrate

To 4.89 g of8,13-epoxy-7β-[N-2-(pyridinylmethyl)aminocarbonyloxy]-1α,6.beta.,9α-trihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal was added 196 ml of a 3/1 mixture of methanol/water. The solutionwas stirred at 60°-70° for 48 hrs. The solution was then concentrated.The residue was flash chromatographed, employing 35% acetone/hexane, andthe appropriate fractions were combined and concentrated. The residuewas dissolved in ether and etheral hydrochloride was added. Theprecipitate was filtered and dried at 110° for 2 hrs to provide 2.27 g(48%) of product, mp 178°-180°.

ANALYSIS: Calculated for C₂₇ H₄₁ ClN₂ O₈ : 58.21%C, 7.42%H, 5.03%N.Found: 57.96%C, 7.12%H, 4.98%N.

EXAMPLE 818,13-Epoxy-7β-(4-methylpiperazino)carbonyloxy-1α,6β,9.alpha.-trihydroxylabd-14-en-11-one

A solution of 1.84 g of8,13-epoxy-7β-(4-methylpiperazino)carbonyloxy-1α,6β,9.alpha.-trihydroxylabad-14-en-11-one-1,9-dimethylformamideacetal in 80 ml of methanol/water (3/1) was stirred at 60°-70° for 48 hrunder nitrogen. The suspension was allowed to cool to room temperature.The precipitate was collected by filtration and dried at 40° (2 mm) for3 hr to provide 0.94 g (56.9%) of product, mp 254°-259°.

ANALYSIS: Calculated for C₂₆ H₄₂ N₂ O₇ : 63.13%C, 8.56%H, 5.67%N. Found:63.26%C, 8.55%H, 5.68%N.

EXAMPLE 828,13-Epoxy-7β-[N-(3-dimethylaminopropyl)aminocarbonyloxy]-1α,6.beta.,9α-trihydroxylabd-14-en-11-onehydrochloride hydrate

8,13-Epoxy-7β-[N-(3-dimethylaminopropyl)aminocarbonyloxy]-1α,6.beta.,9α-trihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal (1.5 g) was dissolved in 50 ml of methanol and 16 ml of water.The mixture was heated at 60° for 72 hrs and allowed to cool. Thereaction mixture was extracted with ethyl acetate and the ethyl acetateextracts were washed with saturated sodium chloride solution, dried overanhydrous sodium sulfate, and filtered. The solvent was removed underreduced pressure and the residue was chromatographed on silica gel. Thecolumn was eluted with 10% methanol/dichloromethane. The appropriatefractions were isolated and the solvent was evaporated. The residue wasdissolved in ether and ethereal hydrogen chloride was added. Thehydrochloride salt was dried under vacuum to give 575 mg (40%) ofproduct, mp 147°-150°.

ANALYSIS: Calculated for C₂₆ H₄₇ ClN₂ O₈ : 56.55%C, 8.61%H, 5.08%N.Found: 56.46%C, 8.43%H, 5.08%N.

EXAMPLE 838,13-Epoxy-7β-[N-(2-dimethylaminoethyl)aminocarbonyloxy]-1α,6.beta.,9α-trihydroxylabd-14-en-11-onehydrochloride

8,13-Epoxy-7β-[N-(2-dimethylaminoethyl)aminocarbonyloxy]-1α,6.beta.,9α-trihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal (1.5 g) was dissolved in 50 ml of methanol and 16 ml of water.The resulting mixture was heated at 55°-60° for 96 hrs. The reactionmixture was allowed to cool to room temperature, extracted with ethylacetate and the ethyl acetate extracts were washed with saturated sodiumchloride. The organic layer was dried over anhydrous sodium sulfate,filtered and the solvent was evaporated. The residue was chromatographedon silica gel. The column was eluted with 40% methanol/methylenechloride. The appropriate fractions were collected and the solvent wasevaporated. The residue was dissolved in a minimum amount oftetrahydrofuran, diluted with ether and ethereal hydrogen chloride wasadded to give, 660 mg (45%) of product, mp 240°.

ANALYSIS: Calculated for C₂₅ H₄₃ ClN₂ O₇ : 57.83%C, 8.36%H, 5.39%N.Found: 57.74%C, 8.53%H, 5.46%N.

EXAMPLE 848,13-Epoxy-7β-[N-2-(2-pyridinylethyl)aminocarbonyloxy]-1α,6.beta.,9α-trihydroxylabd-14-en-11-onehydrochloride

To 1.94 g of7β-[N-2-(2-pyridinylethyl)aminocarbonyloxy]-1α,6β,9α-trihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal was added 78 ml of a 3/1 mixture of methanol/water. The solutionwas stirred at 60°-70° under nitrogen for 65 hrs. The solution wasconcentrated. The residue was flash chromatographed, employing 30%acetone/hexane. To 0.78 g of the residue (1.20 g) dissolved in ether wasadded ethereal hydrogen chloride. The precipitate was collected anddried at 110° for 2 hrs to provide 0.64 g (52%) of product, mp 172°.

ANALYSIS: Calculated for C₂₈ H₄₁ ClN₂ O₇ : 60.80%C, 7.47%N, 5.07%N.Found: 60.62%C, 7.59%H, 5.04%N.

EXAMPLE 858,13-Epoxy-6β-[4-(pyridinylmethyl)aminocarbonyloxy]-1α,7β,9α-trihydroxylabd-14-en-11-one

6β-[4-Pyridylmethyl)aminocarbonyloxy-1α,7β,9α-trihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal (1.2 g) was dissolved in 50 ml of methanol and 16 ml of water.The mixture was heated at 60° for 96 hrs and allowed to cool to roomtemperature. The mixture was extracted with methylene chloride. Theextracts were dried over anhydrous sodium sulfate, filtered, and thesolvent was evaporated. The residue was crystallized from hexane/ethylacetate to give 1.04 g (95%) of product, mp 240°.

ANALYSIS: Calculated for C₂₇ H₃₈ N₂ O₇ : 64.51%C, 7.63%H, 5.57%N. Found:64,385C, 7.67%H, 5.62%N.

EXAMPLE 868,13-Epoxy-6β-(4-methylpiperazinylcarbonyloxy)-1α,7β,9.alpha.-trihydroxylabd-14-en-11-onehydrochloride

8,13-Epoxy-6β-(4-methylpiperazinylcarbonyloxy)-1α,7β,9.alpha.-trihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal (2.3 g) was dissoved in 50 ml of methanol and 15 ml of water. Themixture was heated at 60° for 72 hrs. The mixture was cooled to roomtemperature and stirred overnight. The precipitate was collected anddried to give 1.65 g (79%) of product. A portion of the precipitate (350mg) was dissolved in ether and etheral hydrogen chloride was added untilsolution became acidic. The hydrochloride had mp>260°.

ANALYSIS: Calculated for C₂₆ H₄₃ ClN₂ O₇ : 58.78%C, 8.18%H, 5.27%N.Found: 58.79%C, 8.22%H, 5.13%N.

EXAMPLE 878,13-Epoxy-7β-[N-(2-methylacryloyloxy)aminocarbonyloxy]-1α,6.beta.,9α-trihydroxylabd-14-en-11-one

To a stirred solution of 240 mg of methylacrylic acid in 50 ml ofmethylene chloride was added 283 mg of triethylamine. The mixture wascoolded to 0° in an ice/water bath and stirred for 0.5 hr after 332 mgof trimethylacetyl chloride was added.8,13-Epoxy-7β-(hydroxyaminocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one(1.10 g) and 34 mg of 4-dimethylaminopyridine dissolved in 10 ml oftetrahydrofuran and 50 ml of methylene chloride was added to thereaction mixture. The mixture was stirred for 1 hr at 0°, washed withwater, 0.01N hyrochloric acid and saturated sodium bicarbonate solution.The organic layer was dried over anhydrous sodium sulfate, filtered andthe solvent was evaporated. The residue was chromatographed on silicagel. The column was eluted with hexane ethyl acetate (2/1). Theappropriate fractions were collected and the solvent was evaporated togive 550 mg (48%) of product, mp 103°-106°.

ANALYSIS: Calculated for C₂₅ H₃₇ NO₉ : 60.57%C, 7.54%H, 2.83%N. Found:60.70%C, 7.62%H, 2.66%N.

EXAMPLE 888,13-Epoxy-7β-[N-methyl-N-(4-methylpiperidinyl)carbonyloxyaminocarbonyloxy)9-1α,6β,9α-trihydroxylabd-14-en-11-one hydrochloride hydrate

To a stirred suspension of 242 mg of 4-methylpiperidin-4-ylcarboxylicacid in 25 ml of methylene chloride was added 0.2 ml of triethyl amine.The mixture was stirred for 0.5 hr before 220 mg of1,1'-carbonyldiimidazole was added. After stiring under nitrogen for anadditional 45 mins,8,13-expoxy-7β-(hydroxyaminocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one(500 mg) in 25 ml of methylene chloride was added dropwise. The mixturewas stirred for 16 hrs. The reaction mixture was washed with 0.01Nhydrochloric acid, saturated sodium bicarbonate solution and water. Theorganic layer was dried over anhydrous sodium sulfate, filtered and thesolvent was evaporated. The residue dissolved in ether, and etherealhydrogen chloride was added to the solution. The precipitate wascollected and dried at 60° under vacuum to give 265 mg (377%) ofproduct, mp 174°.

ANALYSIS: Calculated for C₂₉ H₄₉ ClN₂ O₁₀ : 56.05%C, 7.96%H, 4.51%N.Found: 55.97%C, 7.92%H, 4.57%N.

EXAMPLE 897β-[N-(3-Dimethylaminopropionyloxy)aminocarbonyloxy]-1α,6β,9α-trihydroxylabd-14-en-11-onehydrochloride hydrate

To a stirred solution of 2.0 g of8.13-epoxy-7β-(hydroxyaminocarbonyloxy)-1α,6β,9α-trihydroxylabd--14-en-11-one,0.57 g of triethylamine in 50 ml of dichloromethane and 10 ml oftetrahydrofuran at 0° was added 57 mg of 4-dimethylaminopyridine,followed by 711 mg of 3-chloropropionyl chloride in 50 ml ofdichloromethane. The reaction mixture was stirred at 0° for 3.0 hrs anda room temperature for 15 hrs. The reaction mixture was washed with0.01N hydrochloric acid (2×20 ml), saturated sodium bicarbonatesolution, and water. The organic layer was dried over anhydrous sodiumsulfate, filtered, and the solvent was evaporated under reduced pressureto provide7β-[N-(3-chloropropionyloxy)aminocarbonyloxy]-1α,6β,9.alpha.-trihydroxylabd-14-en-11-one,after flash chromatography on silica gel, eluting the column withhexane/ethyl acetate (2:1).

To a stirred suspension of 75.6 mg of dimethylamine hydrochloride in 5ml of dichloromethane was added 187 mg of triethylamine. The solutionwas added to a stirred mixture of 400 mg of7β-[N-(3-chloropropionyloxy)aminocarbonyloxy]-1α,6β,9.alpha.-trihydroxylabd-14-en-11-onein 10 ml of methylene chloride and 0°. The mixture was stirred for 0.5hr under a nitrogen atmosphere. The mixture was then diluted withdichloromethane, and the solution was washed with water, 0.01Nhydrochloric acid and saturated sodium bicarbonate solution. The organicphase was dried over anhydrous sodium sulfate, filtered and the filtratewas evaporated. The residue was dissolved in ether and ethereal hydrogenchloride was added to provide 230 mg (53%) of product, mp 144°-146°.

ANALYSIS: Calcuated for C₂₆ H₄₅ ClN₂ O₁₀ : 53.72%C, 7.64%H, 4.82%N.Found: 53.71%C, 7.78%H, 4.79%N.

EXAMPLE 907β-[N-(trans-3-Chloroacryloyloxy)aminocarbonyloxy]-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-onehydrochloride

To a stirred solution of 298 mg of trans-3-chloroacrylic acid in 50 mlof methylene chloride at 0° was added 282 mg of triethylamine followedby 332 mg of trimethylacetyl chloride. The reaction mixture was stirredat 0° under a nitrogen atmosphere for 0.5 hr and then 1.0 g of8,13-epoxy-7β-(hydroxyaminocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11onedissolved in 10 ml of tetgrahydrofuran and 50 ml of methylene chloridewas added. The mixture was stirred overnight at room temperature.4-Dimethylaminopyridine (34 mg) was added and the mixture was stirred anadditional 2.5 hrs. The mixture was washed with water, 0.01Nhydrochloric acid and saturated sodium bicarbonate solution. The organiclayer was dried over anhydrous sodium sulfate, filtered and the solventevaporated under reduced pressure. The residue was chromatographed onsilica gel. The column was eluted with hexane/ethyl acetate (2:1). Theappropriate fractions were isolated and the solvent evaporated to give300 mg (17.3%) of product, mp 105°-110°.

ANALYSIS: Calculated for C₂₄ H₃₄ ClNO₉ : 55.84%C. 6.65%H, 2.71%N. Found:55.57%C, 6.77%H, 2.54%N.

EXAMPLE 918,13-Epoxy-7β-(N-methylaminocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one-1,9-carbonate

To a stirred solution of 5.0 g of8,13-epoxy-7β-(N-methylaminocarbonyloxy)-1α,6β,9α-trihydroxylabd--14-en-11-onein 200 ml of pyridine at 0° was added dropwise a solution of 50 ml of20% phosgene in toluene. The reaction mixture was stirred for 1 hr at 0°and allowed to warm to room temperature over 1 hr. The reaction mixturewas poured into ice/ethyl acetate/water, extracted twice with ethylacetate, washed with cold 5% hydrochloric acid until the washings wereacidic, washed with saturated sodium chloride solution, dried overanhydrous sodium sulfate, filtered, and evaporated. To a stirredsolution of the residue in 50 ml of dry pyridine at 0° was addeddropwise a solution of 12.5 ml of 20% phosgene in toluene. The mixturewas stirred at ice bath temperature of 0.5 hr and at room temperaturefor 0.5 hr. The reaction mixture was then poured into ice/water/ethylacetate, extracted twice with ethyl acetate, washed with cold 5 %hydrochloric acid until acidic, washed with saturated sodium chloridesolution, dried over anhydrous sodium sulfate, filtered andconcentrated. The residue was dissolved in a minimum volume of ethylacetate and flash chromatographed on silica gel, eluting with 30% ethylacetate/hexane followed by 40% ethyl acetate/hexanes. Concentration ofthe appropriate fractions provided 4.19 g (79.2%) of product. Severalmilligrams of the material was recrystallized from ethylacetate/cyclohexane to provide the analytical product having mp137°-141°.

EXAMPLE 928,13-Epoxy-6β,7β-bis(1-imidazoloylcarbonyloxy)-1α,9α-dihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal

To a stirred solution of 3.0 g of8,13-epoxy-1α,6β,7β,9α-tetrahydroxylabd-14-en-11-one-1,9-dimethylformamideacetal in 60 ml of ethyl acetate was added 2.76 g of1,1'-carbonyldiimidazole. The solution was stirred at room temperatureovernight. The solution was concentrated. The residue was dissolved inethyl acetate and flash chromatographed on silica gel, eluting with 60%ethyl acetate/hexane, followed by 80% ethyl acetate/hexane. Theappropriate fractions were combined and concentrated to provide 2.26 g(52%) of product, mp 110°.

ANALYSIS: Calculated for C₃₁ H₄₁ N₅ O₈ : 60.87%C, 6.76%H, 11.45%N.Found: 60.42%C, 6.88%H, 11.32%N.

EXAMPLE 938,13-Expoxy-7β-[N,N-bis(2-hydroxyethylamino)carbonyloxy]-1α,6.beta.,9α-trihydroxylabd-14-en-11-one

A solution of 0.2 g of8,13-epoxy-7β-[N,N-bis(2-hydroxyethylamino)carbonyloxy]-1α,6.beta.,9α-trihydroxylabad-14-en-11-one-1,9-dimethylformamideacetal, 5 ml of methanol and 5 ml of 80% acetic acid was stirred at roomtemperature under nitrogen for 48 hr. The solution was diluted withethyl acetate, washed twice with water and once with saturated sodiumchloride solution. The solution was dried over anhydrous sodium sulfate,filtered and concentrated. The residue was dissolved in a minimum volumeof 80% ethyl acetate/hexanes and flash chromatographed on silica gel.Concentration of the appropriate fractions provided 106 mg (59%) ofproduct, mp 90°-113°.

ANALYSIS: Calculated for C₂₅ H₄₁ NO₉ : 60.10%C, 8.27%H, 2.80%N. Found:60.12%C, 8.29%H, 2.59%N.

EXAMPLE 948,13-Epoxy-1α,6β,7β,9α-tetrahydroxylabd-14-en-11-one-6,7-carbonate1,9-dimethylformamide acetal

8,13-Epoxy-1α,6β,7β,9α-tetrahydroxylabd-14-en-11-one-1,9-dimethylformamideacetal-1,9-dimethylformamide acetal (1.059 g) in 25 ml of toluenecontaining 0.50 g of 1,1'-carbonyldiimidazole and 0.55 ml oftriethylamine was heated under reflux for 3 hr. The reaction mixture wasevaporated and applied to a flash chromatography column. Elution with50% ethyl acetate/hexane gave 0.976 g (87%) of product. An analyticalsample obtained by recrystallization from hexane had mp 138°-140°.

ANALYSIS: Calculated for C₂₄ H₂₅ NO₇ : 64.12%C, 7.85%H, 3.12%N. Found:63.91%C, 7.98%H, 3.08%N.

EXAMPLE 957β-Acetoxy-1α,9α-dihydroxy-6β-[N-(2-dimethylaminoethyl)aminocarbonyloxy]-8,13-epoxylabd-14-en-11-one-1,9-dimethylformamideacetal

To 5.07 g of8,13-epoxy-1α,6β,7β,9α-tetrahydroxylabd-14-en-11-one-1,9-dimethylformamideacetal in 100 ml of dichloromethane was added 2.33 g of1,1'-carbonylidiimidazole and 3.4 ml of triethylamine. The solution wasstirred for 24 hrs under nitrogen. After addition of 6.62 ml ofN,N-dimethylethylenediamine, the solution was stirred for an additional72 hrs under nitrogen. The solution was poured into a mixture ofice/water/ethyl acetate and extracted with ethyl acetate. The organicextracts were washed with water and saturated sodium chloride solution,dried over anhydrous sodium sulfate, filtered, and concentrated. Theresidue was purified by flash chromatography employing ethyl acetate asthe eluent. The appropriate fractions were combined and concentrated toprovide 3.13 g (49%) of8,13-epoxy-6β-[N-(2-dimethylamino)ethylaminocarbonyloxy]-1α,7.beta.,9α-trihydroxylabd-14-en-11-one-1,9-dimethylformamideacetal. To a solution of 0.10 g of the 1,9-dimethylformamide acetal, soprepared, in 2 ml of dichloromethane was added 0.022 ml of aceticanhydride. To the solution was added 0.0024 g of4-dimethylaminopyridine. The reaction mixture was stirred for 2 hrs atroom temperature, under nitrogen. An additional 0.021 g of4-dimethylaminopyridine was added, and the solution was stirred for 24hrs at room temperature, under nitrogen. The solution was concentratedand purified by flash chromatography, employing 10%methanol/dichloromethane. The appropriate fractions were combined andconcentrated to provide product. The hydrochloride salt, prepared byaddition of ethereal hydrogen chloride to a solution of the product inether, had mp 136°-138°. ##STR37##

We claim:
 1. A compound of the formulawherein: (a) R₁ is hydrogen; (b)R₉ is hydrogen; (c) R₆ and R₇ independently are hydrogen, a group of theformula ##STR38## wherein R₂₀ is hydrogen or loweralkyl of 1 to 6 carbonatoms, or a group of the formula ##STR39## wherein R₁₃ is hydrogen,loweralkyl of 2 to 6 carbon atoms, hydroxyloweralkyl of 1 to 6 carbonatoms, loweralkoxyloweralkyl having 1 to 6 carbon atoms in the alkoxygroup and 2 to 6 carbon atoms in the alkyl group; or a group of theformula HOCH₂ CH(OH)CH₂ --; R₁₄ is hydrogen, hydroxyl, loweralkoxy of 1to 6 carbon atoms, loweralkyl of 1 to 6 carbon atoms, hydroxyloweralkylof 2 to 6 carbon atoms, loweralkoxyloweralkyl of 1 to 6 carbon atoms inalkoxy group and 2 to 6 carbon atoms in the alkyl group, loweralkanoylof 2 to 6 carbon atoms, loweralkanoyllooeralkyl of 2 to 6 carbon atomsin the alkanoyl group and 1 to 6 carbon atoms in the alkyl group,a groupof the formula --(CH₂)_(t) NR₂₁ R₂₂ wherein R₂₁ and R₂₂ areindependently loweralkyl of 1 to 6 carbon atoms and t is 0, or 2 to 6, agroup of the formula OR₂₃ wherein R₂₃ is hydrogen, loweralkyl of 1 to 6carbon atoms, a group of the formula (CH₂)_(t') NR₂₁ R₂₂ wherein t' is 2to 6, R₂₁ and R₂₂ are as above, a group of the formula ##STR40## whereinR₂₄ is hydrogen, loweralkyl of 1 to 6 carbon atoms, lowercycloalkyl of 3to 6 carbon atoms, loweralkenyl of 2 to 6 carbon atoms, haloloweralkenylof 2 to 6 carbon atoms, loweralkanoylloweralkyl of 2 to 6 carbon atomsin the alkanoyl group and 1 to 6 carbon atoms in the alkyl group,loweralkoxyloweralkyl of 1 to 6 carbon atoms in each group,loweralkoxycarbonylloweralkyl of 1 to 6 carbon atoms in each group,loweralkylamino of 1 to 6 carbon atoms, lowerdialkylamino of 2 to 6carbon atoms, a group of the formula (CH₂)_(u) N(R₂₅)COR_(26') wherein uis 1, 2 or 3 and R₂₅ and R₂₆ are independently hydrogen or loweralkyl of1 to 6 carbon atoms, a group of the formula ##STR41## wherein R₂₇ andR_(28') are loweralkyl of 1 to 6 carbon atoms, with the provisos: (e)that R₁, R₆ and R₇ are not simultaneously hydrogen, (f) that when R₁ andR₆ are hydrogen, R₇ is not ##STR42## (g) that R₆ and R₇ are notsimultaneously ##STR43## (h) that when r is 1, either R₆ or R₇ is##STR44## (i) that when R₁ and R₆ are hydrogen, R₁₃ or R₁₄ are notsimultaneously loweralkyl of 1 to 6 carbon atoms, and (h) that when R₁and R₉ taken together from a group of the formula CO, SO, or CHNR₁₁ R₁₂,R₆ and R₇ are not simultaneously hydrogen; the optical or geometricisomers thereof; or the pharmaceutically acceptable salts thereof.
 2. Acompound according to claim 1 wherein R₁ is hydrogen and R₇ is a groupof the formula ##STR45## wherein R₁₃ and R₁₄ are as above.
 3. A compoundaccording to claim 1 wherein R₁ is hydrogen and R₆ is a group of theformula ##STR46## wherein R₁₃ and R₁₄ are as above.
 4. A compoundaccording to claim 2 wherein R₆ and R₁ are hydrogen, R₁₃ is hydrogen andR₁₄ is loweralkyl of 1 to 6 carbon atoms.
 5. A compound according toclaim 1 wherein R₆ is a group of the formula ##STR47## wherein R₁₃ andR₁₄ are as above and R₇ is a group of the formula ##STR48## wherein R₂₀is as above.
 6. A compound according to claim 1 wherein R₇ is a group ofthe formula ##STR49## wherein R₁₃ and R₁₄ are as above and R₆ is a groupof the formula ##STR50## wherein R₂₀ is as above.
 7. The compoundaccording to claim 2 which is7β-(aminocarbonyloxy)-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one.8. The compound according to claim 4 which is8,13-epoxy-7β-(N-methylaminocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one.9. The compound according to claim 2 which is8,13-epoxy-7β-(2-hydroxyethylaminocarbonyloxy)-1α,6≢6.beta.,9α-trihydroxylabd-14-en-11-one.10. The compound according to claim 2 which is8,13-epoxy-7β-(N-2,3-dihydroxypropylaminocarbonyloxy)-1α,6.beta.,9α-trihydroxylabd-14-en-11-one.11. The compound according to claim 2 which is8,13-epoxy-7β-(N-hydroxyaminocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one.12. The compound according to claim 2 which is8,13-epoxy-7β-(N-methylhydroxylaminocarbonyloxy)-1α,6β,9.alpha.-trihydroxylabd-14-en-11-one.13. The compound according to claim 2 which is8,13-epoxy-7β-(N-ethylaminocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one.14. The compound according to claim 2 which is8,13-epoxy-7β-(N-methoxyaminocarbonyloxy)-1α,6⊕,9α-trihydroxylabd-14-en-11-one.15. The compound according to claim 2 which is8,13-epoxy-7β-[N,N-bis(2-hydroxyethylamino)carbonyloxy]-1α,6.beta.,9α-trihydroxylabd-14-en-11-one.16. The compound according to claim 3 which is8,13-epoxy-6β-(N-methylaminocarbonyloxy)-1α,7β,9α-trihydroxylabd-14-en-11-one.17. A method of reducing intraocular pressure in mammals effectivecomprising administering to a mammal requiring intraocular pressurereduction, an intraocular pressure reducing effective amount of acompound of claim
 1. 18. An intraocular pressure reducing compositioncomprising an inert adjuvant and as the active ingredient, aninntraocular pressure reducing effective amount of a compound ofclaim
 1. 19. A compound of claim 2 which is8,13-epoxy-7β-(N-propionylaminocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one.20. A compound of claim 2 which is8,13-epoxy-7β-[N-(4-methoxysuccinyl)oxyaminocarbonyloxy]-1α,6.beta.,9α-trihydroxylabd-14-en-11-one.21. A compound of claim 2 which is8,13-epoxy-7β[N-(N',N'-(dimethylcarbamoyloxy)amino)carbonyloxy]-1.alpha.,6β,9α-trihydroxylabd-14-en-11-one.22. A compound of claim 2 which is8,13-epoxy-7β-[N-2,2-(dimethylpropionyloxy)aminocarbonyloxy]-1α,6β,9α-trihydroxylabd-14-en-11-one.23. A compound of claim 2 which is8,13-epoxy-7β-(N-propylaminocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one.24. A compound of claim 2 which is8,13-epoxy-7β-(N-acetoxyaminocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one.25. A compounnd of claim 2 which is8,13-epoxy-7β-(N-propionyloxyaminocarbonyloxy)-1α,6β,9.alpha.-trihydroxylabd-14-en-11-one.26. A compound of claim 2 which is8,13-epoxy-7β-[N-(2-methylpropionyloxy)aminoicarbonyloxy]-1α,6.beta.,9α-trihydroxylabd-14-en-11-one.27. A compound of claim 2 which is8,13-epoxy-7β-[N-(3-hydroxypropyl)aminocarbonyloxy]-1,α6,β9α-trihydroxylabd-14-en-11-one.28. A compound of claim 2 which is8,13-epoxy-7β-(N-propionyloxy-N-methylaminocarbonyloxy)-1α,6.beta.,9α-trihydroxylabd-14-en-11-one.29. A compound of claim 2 which is8,13-epoxy-7β-[N-(2-oxopropyl)aminocarbonyloxy]-1α,6β,9.alpha.-trihydroxylabd-14-en-11-one.30. A compound of claim 2 which is7β-(N-cyclopropylcarbonyloxyaminocarbonyloxy)-1α,6β,9.alpha.-trihydroxylabd-14-en-11-one.31. A compound of claim 2 which is8,13-epoxy-7β-[N-(2-methoxy-2-methylpropionyloxy)aminocarbonyloxy]-1.alpha.,6β,9α-trihydroxylabd-14-en-11-one.32. A compound of claim 2 which is7β-[N-(3,3-dimethylacryloxyloxy)aminocarbonyloxy[-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one.33. A compound of claim 2 which is8,13-epoxy-7β-[N-(3-methoxyacetoxy)aminocarbony]-1α,6β,9.alpha.-trihydroxylabd-14-en-11-one.34. A compound of claim 3 which is6β-(aminocarbonyloxy)-,8,13-epoxy-1α,7β,9α-trihydroxylabd-14-en-11-one.35. A compound of claim 2 which is7β-[N-(3-oxobutenyl)oxyaminocarbonyloxy]-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one.36. A compound of claim 2 which is7β-(N-acrylolyoxyaminocarbonyloxy)-8,11-epoxy-1α,6β,9.alpha.-trihydroxylabd-14-en-11-one.37. A compound according to claim 3 which is8,13-epoxy-6β-[N-(2-hydroxyethyl)aminocarbonyloxy]-1α,7β,9α-trihydroxylabd-14-en-11-one.38. A compound according to claim 3 which is6β-(N,N-dimethylaminocarbonyloxy)-1α,7β,9α-trihydroxylabd-14-en-11-one.39. A compound according to claim 2 which is8,13-epoxy-7β-(N-ethoxyaminocarbonyloxy)-1α,6β,9α-trihydroxylabd-14-en-11-one.40. A compound according to claim 1 which is7β-(aminocarbonyloxy)-1α-(N-t-butylaminoacetoxy)-6β,9.alpha.-dihydroxy-8,13-epoxylabd-14-en-11-onehydrochloride.
 41. A compound according to claim 2 which is7β-[N-(N-acetylglycyloxy)aminocarbonyloxy]-8,13-epoxy-1α,6.beta.,9α-trihydroxylabd-14-en-11-one.42. A compound according to claim 2 which is7β-[N-(4-dimethylaminobutyryloxy)aminocarbonyloxy]-8,13-epoxy-1.alpha.6β,9α-trihydroxylabd-14-en-11-one.43. A compound according to claim 5 which is8,13-epoxy-6β-(hydoxylaminocarbonyloxy)-1α,7β,9α-trihydroxylabd-14-en-11-one.44. A compound according to claim 2 which is8,13-epoxy-7β-[N-(3-dimethylaminopropyl)aminocarbonyloxy]-1α,6.beta.,9α-trihydroxylabd-14-en-11-one.45. A compound according to claim 2 which is8,13-epoxy-7β-[N-(2-dimethylaminoethyl)aminocarbonyloxy]-1α,6.beta.,9α-trihydroxylabd-14-en-11-one.46. A compound according to claim 2 which is8,13-epoxy-7β-[N-(2-methylacryloyloxy)aminocarbonyloxy]-1α,6.beta.,9α-trihydroxylabd-14-en-11-one.47. A compound according to claim 2 which is7β-[N-(3-dimethylaminopropiuonyloxy)aminocarbonyloxy]-1α,6.beta.,9α-trihydroxylabd-14-en-11-one.48. A compound according to claim 2 which is7β-[N-trans-3-chloroacryloyloxy)aminocarbonyloxy]-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one.49. A compound according to claim 2 which is8,13-epoxy-7β-[N,N-bis(2-hydroxyethylamino)carbonyloxy-1α,6.beta.,9α-trihydroxylabd-14-en-11-one.